That’s the new buzz here:
The vast majority of people believe that there are only two alternative ways to explain the origins of biological diversity. One way is Creationism that depends upon supernatural intervention by a divine Creator. The other way is Neo-Darwinism, which has elevated Natural Selection into a unique creative force that solves all the difficult evolutionary problems. Both views are inconsistent with significant bodies of empirical evidence and have evolved into hard-line ideologies. There is a need for a more open “third way” of discussing evolutionary change based on empirical observations.
Supporters include Shapiro, Noble, Koonin, Neuman, Jablonka—non-Darwin lobby researchers into evolution. Interested in understanding nature, not getting a judge to agree to enshrine their beliefs in a tax-funded, union-infested school system.
Sounds interesting. Stuff to get started.
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There is no third way to explain evolution, and I doubt (though I am of course just speculating) any of these scientists really believe they are going to find a reasonable scientific explanation apart from Darwinism or design: we are not talking about explaining earthquakes, for goodness sakes, we are talking about explaining hearts, lungs, brains and human consciousness! They just realize that Darwinism is nonsense are honest enough to admit it, but can’t accept design as a scientific theory (or in some cases perhaps, just don’t want to admit it publically—again I am speculating, based on personal conversations with other scientists and mathematicians). So I think the third “way” is not really a third way to explain evolution, it is a third way to talk about it: admit you don’t understand evolution, but don’t accept design. And yes, we should certainly welcome these people, admitting that you don’t know something when you really don’t know is a refreshing new “way” to talk about evolution.
IOW, let’s invent a compatibilist evolutionary narrative because we need to steal some concepts otherwise unavailable to materialist/physicalist/naturalist ideology.
Nagel’s hypothesis largely rests upon his HOPE that their is no Designer. He has explicitly admitted that he does not want there to be a god.
Here is another one:
http://www.macroevolution.net/
Or is that just evo-devo?
Or they could consider IDvolution.org – God “breathed” the super language of DNA into the “kinds” in the creative act.
This accounts for the diversity of life we see. The core makeup shared by all living things have the necessary complex information built in that facilitates rapid and responsive adaptation of features and variation while being able to preserve the “kind” that they began as. Life has been created with the creativity built in ready to respond to triggering events.
Since it has been demonstrated that all living organisms on Earth have the same core, it is virtually certain that living organisms have been thought of AT ONCE by the One and the same Creator endowed with the super language we know as DNA that switched on the formation of the various kinds, the cattle, the swimming creatures, the flying creatures, etc.. in a pristine harmonious state and superb adaptability and responsiveness to their environment for the purpose of populating the earth that became subject to the ravages of corruption by the sin of one man (deleterious mutations).
IDvolution considers the latest science and is consistent with the continuous teaching of the Church.
What an intriguing concept. I presume that the “third way” is that somehow simple life “evolved” the ability to strategically edit their own DNA. Of course they did so before the development of the Eukaryota. No problem. Perfectly reasonable.
The notable thing here is that pro evolution researchers are admitting their is important problems with evolution. Surely creationisms influence is having a effect. they say there is a third way but thats not a hypothesis yet.
in fact the bible simply is fine still and dArwin s is coming unglued in modern times.
yes there are other mechanisms in biology not yet discovered as God did all creation on week one. yEt biology has done great things since. People looks being case in point.
these people are okay to frustrate evolution but still they are not sharp enough to see YEC/ID are the ones actually on the right trail.
i’m not sending money.
Moose Dr,
you made the point i was thinking about… I read about James Shapiro’s natural genetic engineering (NGE) (and the third way idea by the way) about a year ago (here’s that article, by the way – http://new.bostonreview.net/BR22.1/shapiro.html ).
Indeed how is the existence of such an ability as NGE explained? It’s not simply a program contained somewhere in DNA or elsewhere, it possesses properties of intelligence! It can act purposefully, it can create new functional information… Is it the new hero who can turn frogs into princesses?
And how did that amazing NGE come about? Will the answer be “by chance”?
The 3rd. Way should be able to explain the origin of this:
http://www.biosciencetechnolog.....8;type=cta
The 3rd. Way should be able to explain the origin of this:
The 3rd. Way should figure out the origin of this:
http://jcb.rupress.org/content/205/4/430.3
The 3rd. Way should be able to figure out the origin of this:
Since the first and second ways can’t figure out the origin of all that complicated stuff, maybe the third way will do it? If not, then someone will come up with a fourth way. Or a fifth, sixth, seventh way?
With the data avalanche flooding bioinformatics centers, and more data coming out of research labs at an increasing rate, they should have plenty of information to figure it out.
Or could this all be part of the unending revelation of the ultimate reality?
First science should figure out how all these complex things work, before worrying about how they came to be. The 3rd. Way can work on the latter part.
“Recent studies are shaping current thinking on how…
and how…”
The Energizer bunny ad comes to mind, doesn’t it?
The First Way doesn’t have to figure out the origin of anything, because it is written in their ancient book: Genesis 1:1
And was also written by the people of The Way* in their book: John 1:1-4
(*) The Way is related to The First Way and The Only Way.
Is the second way associated with the scandalous extrapolation of the adaptability mechanisms observed in the Galapagos finch population in the mid 19th century?
The 3td. Way should find the origin of this:
Piece of cake, isn’t it? 😉
The 3rd. Way has to figure out the origin of this, while serious science tries to understand how this works:
The 3rd. Way should figure out the origin of this too:
Piece of cake, isn’t it?
The 3rd. Way folks should try hard to heed the rules for valid research:
Shoddy pseudo-science should not be permitted.
The 3rd. Way should describe how this originated:
The 3rd. Way should figure out the origin of this:
Piece of cake, isn’t it?
The 3rd. Way folks can figure this out right away 😉
The 3rd. Way could work on the origin of this:
What’s the origin of these mechanisms?
More questions for the 3rd. Way folks about origin: how did all this start?
Another question for The Third Way: where did this come from?
Another task for the 3rd way: find the origin of this:
Maybe the ‘third way’ group can figure out the origin of this?
Can the 3rd. way folks explain the origin of this?
Can the 3rd. Way explain the origin of this?
Can the 3rd. Way explain the origin of this?
[although science is busy trying to understand just how this works]
Can the 3rd. way explain the origin of this?
Can the third way explain the origin of this?
Can the 3rd. Way explain the origin of this, while scientists try to understand how this actually works?
Can the 3rd. way explain the origin of this?
Can the 3rd. way explain the origin of this, while scientists try to understand how it works? Piece of cake, isn’t it?
Can the 3rd. way explain the origin of this, while scientists try to understand how it works?
The 3rd. Way may try to explain the origin of this, while scientists try to understand how this works. Is the latter by far more important for medical advance? Is the former just to fuel the ongoing philosophical debates?
The 3rd. Way may try to explain the origin of this, while scientists try to understand how this works. The latter is what may help for medical advance, hence research should focus in on that area.
Can the 3rd. Way explain the origin of these mechanisms? In the meantime, scientists can work hard on trying to understand how these mechanisms work.
Can the 3rd. Way figure out how to explain the origin of these mechanisms, while scientists try to understand their effect and how they work?
Can the 3rd. Way explain the origin of the ‘right’ route(s) to bipolarity and the rest of these mechanisms? In the meantime, scientists could work on trying to understand how they work and what could mess them up.
recent email to The 3rd. Way:
My enormous science-related ignorance compels me to respect the members of The Third Way and recognize their tremendous scientific knowledge and academic experience.
Seriously would like to read their opinions within the ongoing ‘origin’ debate. However, I’m more interested in learning about the way certain biological systems function in their current state, not how they originated.
I strongly believe science should focus in on trying to understand very well how biological systems work, so better medical treatments and preventive programs can be developed and implemented soon.
Can the ‘origin’ discussion produce comparable benefits?
Fortunately, most scientists are busy working on interesting research projects that should discover more details about the wonderful biological systems.
While scientists try to understand these complex mechanisms, the 3rd. way folks could try to explain the origin of those mechanisms.
While scientists try to understand this mystery, the 3rd. Way could try to explain the origin of the mysterious mechanisms.
To the 3rd. way: where did these mechanisms come from? How?
To the researchers: how do these mechanisms work?
The 3rd. Way shouldn’t run out of work, even if all they will do is try to explain the origin of the biological systems, while the scientists try to understand better how those systems function. Here’s an easy one to start from:
Another simple neuroscience case. Maybe the 3rd. way can explain the origin of this, while scientists continue to research the mechanisms behind the functionality of all this stuff?
Hey, they’re getting close, almost there. Just a few more things and bingo! they’ll have all the missing pieces in the biological puzzle. Then finally, the 3rd. way will have it very easy to explain how this all started. But let’s take it easy, no rush, ‘poco a poco’. In the meantime, let the scientists continue their research.
The 3rd. way may want to explain the origin of this, while scientists try to understand it well:
Can the 3rd. way explain the origin of all these mechanisms, while scientists keep trying to understand what they do and how they function?
protein choreography ? This is not about the physical and chemical properties of the individual proteins, not even about the physical or chemical properties that allow the interactions between proteins, because those properties are the same in all choreographies. The question is mainly about their specific coordinated arrangements in space and time, which are different for separate choreographies, so that all things work together to produce the observed specific effects. What steps would it take to put together each of those choreographies?
As analogy, the same ballet dancers can appear in different scenes, and also in different ballet choreographies. The same orchestra, with the same musicians playing on the same instruments, and directed by the same conductor, can produce totally different ballet choreographies.
Protein choreography? How are they put together for different functional situations?
The 3rd. way will have a lot of explaining to do on this 2-year old paper alone. Some of the issues relate to the highlighted text. The questions associated with the highlighted text are implicitly obvious.
Scientists have a lot of research work ahead, to understand how the mechanisms function and their effects. Many outstanding questions to answer. Puzzle missing parts to find.
Interesting mechanisms.
Not a very recent document (4 years old), but still valid.
Important elaborate mechanisms still poorly understood
The 3rd. Way may went to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effect they have.
#58 error correction:
The 3rd. Way could try to explain the origin of this, while scientists try to understand it.
The 3rd. way could try to explain the origin of this, while scientists try to understand it.
The 3rd way may try to investigate the origin of this, while scientists try to understand it better.
Maybe the 3rd way can investigate the origin of this, while scientists keep trying to understand it.
Can the 3rd. way explain the origin of these mechanisms, while scientists keep trying to understand how they work and what they do?
Research tips
Can the 3rd. way explain the origin of these mechanisms, while scientists try to understand how they work?
The 3rd. Way might like some statements in this paper, because they refer to potential ways some mechanisms evolved. However, how solid are these arguments? What evidences are they based on? Let’s itemize the vague descriptions.
The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.
The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.
The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.
The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.
The 3rd. way could try to explain the origin of these mechanisms, while scientists keep trying to understand how these mechanisms work and what effect they have.
the mechanisms referred in previous #67 could be broken down into minimum steps, so that no important questions are left unanswered when trying to explain the origin of those mechanisms. Many questions come to mind when one reads that paper.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
This report -published a couple of years ago- shows that science research is moving ahead very fast these days. Probably today more information is available on this subject, than it was known when this report was published. We look forward with much anticipation to reading more reports on this subject in the coming days. These seem like exciting times to be in science or at least to look at what’s going on in serious science.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
Now, wonder how is this in the human embryo? Looking for that information around. Would prefer to look at the exact process in human development. If you find it, please post the link here. Thanks.
New research discoveries, old assumptions trashed, basic concepts revised,… what else is new? This is science.
Stay tuned, more to come 😉
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
This very interesting Webinar on lncRNAs just finished this afternoon.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they cause.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
Looking back at the last 80 comments, the 3rd. way might want to consider explaining how all the currently known mechanisms ended up working together in biological systems in the manner, timing and sequence they appear to do. Basically, the whole enchilada. Any drink with it? 😉
Hypernaturalism?
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
The 3rd. way may want to explain the origin of these mechanisms, while scientists try to understand how these mechanisms work and what effects they produce.
Maybe these juicy materials will be available before the end of this year?
Call for Papers for a Special Issue on Organogenesis
Call for Papers for a Special Issue on Organogenesis
Guest Editor: Paul Trainor, Stowers Institute
Submission Deadline: August 31, 2014
You are encouraged to submit:
• Research articles exploring mechanisms of organogenesis
• Techniques articles describing new techniques of broad impact
• Disease Connections articles describing novel models/approaches for understanding the developmental basis of disease
• Regeneration/Stem Cell Biology articles describing methods or mechanisms in development/regeneration of any organ system
• Reviews articles or Critical Commentaries
All articles will undergo a thorough peer review to determine their merits for publication.
All special issues and reviews published in Developmental Dynamics are open access immediately upon publication, allowing your work to be disseminated widely throughout the scientific community.
Submit manuscripts online at: http://mc.manuscriptcentral.com/dvdy-wiley
Author Guidelines can be found under ‘for Contributors’ on the left side of the page at http://onlinelibrary.wiley.com.....)1097-0177
Please contact the editorial office (mailto:DVDY@anatomy.org) for additional information and to let us know that you plan to submit a manuscript.
Do we know these brain mechanisms well enough to describe them accurately?
Yes, No, Maybe?
Remember this old song?
Well, here’s a newer version 😉
Here’s a link to the entire article:
Wow! Just noticed I have posted over 100 consecutive comments in this thread without anyone else adding other comments. Perhaps this thread is too boring, or my comments made it unattractive? Hmmm…
BTW, most of the posts after #9 are articles I’m reading for my project on cell fate determination mechanisms. A few are just refreshing reports. I thought other readers would find them interesting too.
“…the cellular processes involved in constructing and organizing the hippocampus remain largely unclear.”
Stem cell energetics
Evolved?
How?
The 3rd. way may want to include this case in their pursue of the ultimate ‘ool’ explanation, while scientists continue to investigate how this develops and functions.
Quite a bit of info to chew and digest here:
More stuff for the 3rd way to figure out in their ool investigation
maybe the 3rd way can demonstrate how this so called ‘evolutionarily conserved’ mechanism originated? in the meantime, scientists will continue to investigate how this whole thing functions
More stuff for the 3rd way to figure out in their ool investigation
Lots of things must be right in order for the whole thing to be right. Very easy to mess things up. Very difficult for the whole thing to work well. How many interrelated functions can we detect in these mechanisms?
how are different cell types generated at specific times and domains throughout embryonic life?
More stuff for the 3rd way to figure out in their ool investigation
Here’s a hint for the 3rd way. Maybe this can help them to figure out the origin of all this stuff?
There are many questions to ask about this paper. Let’s deal with this later.
Something else for the 3rd way to consider in their OOL research.
There are many complex mechanisms in the plants too. More work for the 3rd way in their OOL research.
Interesting, isn’t it?
Interesting mechanisms.
Interesting research to keep an eye on:
Interesting research
Interesting research
Interesting research:
Interesting research
Check this out
chromosome segregation: insights from trypanosomes
Aurora at the pole and equator: overlapping functions of Aurora kinases in the mitotic spindle
Dual mechanisms prevent premature chromosome segregation during meiosis
Exotic mitotic mechanisms
Microtubule plus-ends within a mitotic cell are ‘moving platforms’ with anchoring, signalling and force-coupling roles
interface between centriole and peri-centriolar material
Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex
Dionisio:
Thank you. I needed this!
More information to enjoy
gpuccio,
Glad to know that you can use some information posted in this thread.
A Model of Grid Cell Development through Spatial Exploration and Spike Time-Dependent Plasticity
#148
Rules that govern?
Is that related to GP’s procedures?
Defining the Protein–Protein Interaction Network of the Human Hippo Pathway
lasciatemi cantare!
pathway activity influences cell fate.
signaling pathway in stem cell biology
Dionisio:
I am working hard at the procedures post. I am trying to update about all this important stuff about cell differentiation and regulation, so I am afraid that I will need some more time. But it is worth the while. These things are really fascinating. I am not surprised that they are rarely cited in the neo darwinian framework. But luckily, there is a lot of experimental advanceament available.
Thank you for pointing to so many key issues. You are sparing me a lot of time! 🙂
Take a look at the difficult work this evo-devo scientist is trying to do 😉
Good luck, buddy 😉
Follow-up to 154
Wouldn’t it make more sense to call it devo-evo instead?
First things first. Try figuring out how the whole ‘devo’ thing works before trying to imagine how it came to be.
Ok, it has to do with evolutionary developmental biology, that’s why the name.
Oh, well. Whatever. Who cares? 😉
More on #154
That’s what ‘job security’ was meant to be: a never-ending project 😉
Just to figure out the devo part it should take some time, then the evo part…
Cool!
still on #154
the devo we want to understand is the process going from zygote to adult (from Z to A or briefly Z2A).
get all the devo details first – that’s quite a tremendous task in and by itself, that might require some time to accomplish.
once the devo is well understood, then they could move on to figure out the evo of the devo, if they still want to, because perhaps by the time they get all the pieces of the devo puzzle together in their places, they might not want to look at anything else 😉
does this sound like a plan?
gpuccio,
I look forward to reading your procedures post, but please, take your time to write it well, don’t rush it. That should be a very important post for many to read and discuss. If part 1 has attracted almost 2 thousand visits and close to 500 comments, part 2 might reignite the discussion to a new level.
I’ve been busy traveling and working on other time-consuming issues that distract my attention from the studying.
Biological pacemaker created by minimally invasive somatic reprogramming
Reprogramming? how was the initial programming done?
Insights into the molecular mechanisms underlying diversified wing venation among insects
Evo-devo research fresh from the oven: cleavage clock regulates features of lineage-specific differentiation
Nuclear functions of prefoldin
cell cycle analysis in vivo
Regulation of a novel isoform of Receptor Expression Enhancing Protein REEP6 in rod photoreceptors by bZIP transcription factor NRL
Exploring the Function of Cell Shape and Size during Mitosis
Making the spindle checkpoint strong
Regulating chromosome segregation
Cnn as a scaffold for centrosome maturation
Molecular forces are key to proper cell division
Geometrically Controlled Asymmetric Division of CD4+ T Cells Studied by Immunological Synapse Arrays
Duh! now, can they tell us more details on how it all happened ?
Regulation of motility & cell polarity
Regulation of dynamic cell polarity in bacteria
Cell cycle regulation with an emphasis on chromosome replication & cell division
Regulation of dynamic polarity switching in bacteria by a Ras?like G?protein and its cognate GAP
Stop competing, start talking!
NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane
Apparently, car dealerships now employ ‘motility specialists’, instead of sales people.
Addendum to #177
Axel,
Glad to see your comments in this thread!
Mother Centrioles Do a Cartwheel to Produce Just One Daughter
SAS-6 Assembly Templated by the Lumen of Cartwheel-less Centrioles Precedes Centriole Duplication
Spatial Regionalization and Heterochrony in the Formation of Adult Pallial Neural Stem Cells
Sizing Up Lung Stem Cells
Long Noncoding RNA Modulates Alternative Splicing Regulators in Arabidopsis
The Art of Choreographing Asymmetric Cell Division
Function of the Mitotic Checkpoint
protein She1 appears to play a key role in chromosome- and spindle positioning during asymmetric cell division
Asymmetric cell division is important in the self-renewal of stem cells and because it ensures that daughter cells have different fates and functions.
http://phys.org/print271580403.html
important trigger dictates how cells change their identity and gain specialized functions.
Whole-Genome Analysis of Muscle Founder Cells Implicates the Chromatin Regulator Sin3A in Muscle Identity
Stem cell ageing and non-random chromosome segregation
http://rstb.royalsocietypublis.....nsion.html
Polar delivery in plants; commonalities and differences to animal epithelial cells
maintenance of the Shugoshin Sgo1 at meiotic centromeres does not require Cdc2 activity, whereas localization of the kinase aurora does
http://rsob.royalsocietypublis.....5c4e6ce2e8
The homeodomain transcription factor PITX2 is required for specifying correct cell fates and establishing angiogenic privilege in the developing cornea
Cell?intrinsic timing in animal development
In certain instances we can witness cells controlling the sequence of their behaviors as they divide and differentiate. Striking examples occur in the nervous systems of animals where the order of differentiated cell types can be traced to internal changes in their progenitors. Elucidating the molecular mechanisms underlying such cell fate succession has been of interest for its role in generating cell type diversity and proper tissue structure. Another well?studied instance of developmental timing occurs in the larva of the nematode Caenorhabditis elegans, where the heterochronic gene pathway controls the succession of a variety of developmental events. In each case, the identification of molecules involved and the elucidation of their regulatory relationships is ongoing, but some important factors and dynamics have been revealed. In particular, certain homologs of worm heterochronic factors have been shown to work in neural development, alerting us to possible connections among these systems and the possibility of universal components of timing mechanisms. These connections also cause us to consider whether cell?intrinsic timing is more widespread, regardless of whether multiple differentiated cell types are produced in any particular order.
Advanced Review
Eric G. Moss, Jennifer Romer?Seibert
Published Online: Jul 24 2014
DOI: 10.1002/wdev.145
http://wires.wiley.com/WileyCD.....EV145.html
Timing germ cell development
(Phys.org) —Scientists from the Friedrich Miescher Institute for Biomedical Research identify a novel mechanism in early germ cell development. They show how the chromatin modulator PRC1 coordinates the timing of sexual differentiation of germ cells during embryonic development. The study, which enhances our understanding of the mechanisms regulating stem-ness and cell fate determination
Like all Royal houses in Europe prepare their heirs to the throne, the body carefully develops its germ cells specifically and early on for their sole task of propagating the lineage. As the egg and the sperm fuse to form a zygote, a new being, they look back on an extensive “training” that separated them early on from other cells in the developing embryo. During germ cell development, gene expression programs and chromatin states are prepared such that they support embryonic development after fertilization. What is more, the germ cells have to undergo an unusual type of cell division called meiosis to provide the correct set of chromosomes to the embryo. They have to reduce the two copies of each chromosome – one from the mother, one from the father – to one.
It has long been a mystery what enables germ cells to undergo meiosis. Antoine Peters, senior group leader at the Friedrich Miescher Institute for Biomedical Research and Adjunct Professor at the University of Basel, and his team have now been able to identify a major regulator of this switch in cell fate. As they report in the latest issue of Nature, they could show how the chromatin modifier and transcriptional repressor PRC1 controls the development of primordial germ cells and their entry into meiosis.
http://phys.org/news/2013-03-germ-cell.html
Asymmetric centrosome behavior and the mechanisms of stem cell division
The ability of dividing cells to produce daughters with different fates is an important developmental mechanism conserved from bacteria to fungi, plants, and metazoan animals. Asymmetric outcomes of a cell division can be specified by two general mechanisms: asymmetric segregation of intrinsic fate determinants or asymmetric placement of daughter cells into microenvironments that provide extrinsic signals that direct cells to different states. For both, spindle orientation must be coordinated with the localization of intrinsic determinants or source of extrinsic signals to achieve the proper asymmetric outcome. Recent work on spindle orientation in Drosophila melanogaster male germline stem cells and neuroblasts has brought into sharp focus the key role of differential centrosome behavior in developmentally programmed asymmetric division (for reviews see Cabernard, C., and C.Q. Doe. 2007. Curr. Biol. 17:R465–R467; Gonzalez, C. 2007. Nat. Rev. Genet. 8:462–472). These findings provide new insights and suggest intriguing new models for how cells coordinate spindle orientation with their cellular microenvironment to regulate and direct cell fate decisions within tissues.
doi: 10.1083/jcb.200707083
http://m.jcb.rupress.org/conte.....1.abstract
Cell Polarity Signaling
The 2014 Gordon Research Conference on Cell Polarity Signaling is a forum for discussion at the frontiers of cell polarity research. Cell polarity is a universal biological process that is fundamental to all aspects of cell division, growth, development, and tissue morphogenesis. It is also perturbed in numerous developmental diseases, in aging, and in cancer. Cell polarity underlies the generation of diverse cell types by asymmetrically dividing stem cells, and provides the organizational structures for tissue architecture. The recognition that cell polarity, and defects in polarization, are of such broad biological importance has led to an explosion of interest in this area. Therefore, the conference will cover a broad range of topics from cell polarity in development and cancer, to neural stem cell biology, inheritance of DNA and centrosomes, ciliogenesis and tissue morphogenesis, and will be an excellent opportunity to discuss the latest developments in the field. Key questions to be discussed at the Conference will include the following: How do signaling networks spatially organize the cell into polarized structures? How are these signals used to polarize membrane traffic? Are similar signals and mechanisms used in different contexts, such as in neurons versus epithelial cells, germ cells, or yeast? Does differential inheritance of DNA strands occur in stem cells, and how important is it? How do stem cells orient their mitotic spindles and segregate cell fate determinants? How common is asymmetric cell division in stem/progenitor cells? How important is EMT and/or loss of polarity during cancer initiation and progression? How and why are RNAs polarized within cells? Is differential segregation of damaged proteins between daughter cells important in aging? Participants will include established investigators from disciplines both within and outside the cell polarity field, and participation by young investigators will be strongly emphasized. Poster presentations will take place on each day of the meeting, allowing for widespread participation of conference attendees at all career stages. Speakers will also be selected from the abstracts submitted for poster presentations, to provide opportunities for presentation of the newest findings. We envision that this GRC will facilitate discussion of cutting edge research in cell polarity and will foster collaborations that will help drive the field forward.
http://www.grc.org/programs.as.....=cellpolar
Mechanisms regulating stem cell polarity and the specification of asymmetric divisions
Hila Toledano,
D. Leanne Jones,§
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037
The ability of cells to divide asymmetrically to produce two different cell types provides the cellular diversity found in every multicellular organism. Asymmetric localization of cell-cell junctions and/or intrinsic cell fate determinants and position within specific environment (“niche”) are examples of mechanisms used to specify cell polarity and direct asymmetric divisions. During development, asymmetric divisions provide the basis for establishment of the body axis and cell fate determination in a range of processes. Subsequently, asymmetric cell divisions play a critical role in maintaining adult stem cell populations, while at the same time generating an adequate number of differentiating daughter cells to maintain tissue homeostasis and repair. Loss of cell polarity, and consequently the potential for asymmetric divisions, is often linked to excessive stem cell self-renewal and tumorigenesis. Here we will discuss multiple factors and mechanisms that imbue cells with polarity to facilitate an asymmetric outcome to stem cell divisions, assuring self-renewal and maintenance of the stem cell pool.
Asymmetric division is a property of stem cells that leads to the generation of two cells that can adopt different fates. One has the potential to renew stem cell identity and continue to divide in an asymmetric manner, whereas the other cell will differentiate along a specific lineage. In some cases, factors within the dividing mother cell lead to the differential segregation of cell fate determinants to give two distinct daughters upon division. In others, however, establishment of different fates is reinforced through signaling from neighboring cells. Ultimately, asymmetric divisions are regulated directly by genes that control the process of asymmetric cell division itself or determine the distinct cell fates of the two daughter cells.
http://www.stembook.org/node/562
Asymmetric cell division: from A to Z
Could we say from Z to A instead? from zygote to adult?
Cell divisions producing two daughter cells that adopt distinct fates are defined as asymmetric. In all organisms, ranging from bacteria to mammals, in which development has been studied extensively, asymmetric cell divisions generate cell diversity. Asymmetric cell divisions can be achieved by either intrinsic or extrinsic mechanisms (Fig. 1). Intrinsic mechanisms involve the preferential segregation of cell fate determinants to one of two daughter cells during mitosis. Asymmetrically segregated factors that bind cell fate determinants and orient the mitotic spindle may also be necessary to ensure the faithful segregation of determinants into only one daughter cell.
Extrinsic mechanisms involve cell–cell communication. In metazoans, a dividing’s cell’s social contex provides a wealth of positional information and opportunity for cell–cell interactions. Interactions between daughter cells or between a daughter cell and other nearby cells could specify daughter cell fate. Interaction between a progenitor cell and its environment can also influence cell polarity by directing spindle orientation and the asymmetric distribution of developmental potential to daughter cells. Recent studies have indicated that a combination of intrinsic and extrinsic mechanisms specify distinct daughter cell fates during asymmetric cell divisions.
http://m.genesdev.cshlp.org/co.....25.extract
Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns
Early mammalian embryogenesis is controlled by mechanisms governing the balance between pluripotency and differentiation. The expression of early lineage-specific genes can vary significantly between species, with implications for developmental control and stem cell derivation. However, the mechanisms involved in patterning the human embryo are still unclear. We analyzed the appearance and localization of lineage-specific transcription factors in staged preimplantation human embryos from the zygote until the blastocyst. We observed that the pluripotency-associated transcription factor OCT4 was initially expressed in 8-cell embryos at 3 days post-fertilization (dpf), and restricted to the inner cell mass (ICM) in 128-256 cell blastocysts (6dpf), approximately 2 days later than the mouse. The trophectoderm (TE)-associated transcription factor CDX2 was upregulated in 5dpf blastocysts and initially coincident with OCT4, indicating a lag in CDX2 initiation in the TE lineage, relative to the mouse. Once established, the TE expressed intracellular and cell-surface proteins cytokeratin-7 (CK7) and fibroblast growth factor receptor-1 (FGFR1), which are thought to be specific to post-implantation human trophoblast progenitor cells. The primitive endoderm (PE)-associated transcription factor SOX17 was initially heterogeneously expressed in the ICM where it co-localized with a sub-set of OCT4 expressing cells at 4-5dpf. SOX17 was progressively restricted to the PE adjacent to the blastocoel cavity together with the transcription factor GATA6 by 6dpf. We observed low levels of Laminin expression in the human PE, though this basement membrane component is thought to play an important role in mouse PE cell sorting, suggesting divergence in differentiation mechanisms between species. Additionally, while stem cell lines representing the three distinct cell types that comprise a mouse blastocyst have been established, the identity of cell types that emerge during early human embryonic stem cell derivation is unclear. We observed that derivation from plating intact human blastocysts resulted predominantly in the outgrowth of TE-like cells, which impairs human embryonic stem cell derivation. Altogether, our findings provide important insight into developmental patterning of preimplantation human embryos with potential consequences for stem cell derivation.
doi: 10.1016/j.ydbio.2012.12.008.
http://www.ncbi.nlm.nih.gov/m/.....94/related
Human trophectoderm cells are not yet committed.
doi: 10.1093/humrep/des432.
STUDY QUESTION: Are human trophectoderm (TE) cells committed or still able to develop into inner cell mass (ICM) cells?
SUMMARY ANSWER: Human full blastocyst TE cells still have the capacity to develop into ICM cells expressing the pluripotency marker NANOG, thus they are not yet committed.
WHAT IS KNOWN ALREADY: Human Day 5 full blastocyst TE cells express the pluripotency markers POU5F1, SOX2 and SALL4 as well as the TE markers HLA-G and KRT18 but not yet CDX2, therefore their developmental direction may not yet be definite.
STUDY DESIGN, SIZE, DURATION: The potency of human blastocyst TE cells was investigated by determining their in vitro capacity to develop into a blastocyst with ICM cells expressing NANOG; TE cells were isolated either by aspiration under visual control or after labeling with fluorescent 594-wheat germ agglutinin. Further on, aspirated TE cells were also labeled with fluorescent PKH67 and repositioned in the center of the original embryo.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Human preimplantation embryos were used for research after obtaining informed consent from IVF patients. The experiments were approved by the Local Ethical Committee and the ‘Belgian Federal Committee on medical and scientific research on embryos in vitro’. Outer cells were isolated and reaggregated by micromanipulation. Reconstituted embryos were analyzed by immunocytochemistry.
MAIN RESULTS AND THE ROLE OF CHANCE: Isolated and reaggregated TE cells from full human blastocysts are able to develop into blastocysts with ICM cells expressing the pluripotency marker NANOG. Moreover, the majority of the isolated TE cells which were repositioned in the center of the embryo do not sort back to their original position but integrate within the ICM and start to express NANOG.
LIMITATIONS, REASONS FOR CAUTION: Owing to legal and ethical restrictions, manipulated human embryos cannot be transferred into the uterus to determine their totipotent capacity. The definitive demonstration that embryos reconstructed with TE cells are a source of pluripotent cells is to obtain human embryonic stem cell ‘like’ line(s), which will allow full characterization of the cells.
WIDER IMPLICATIONS OF THE FINDINGS: Our finding has important implications in reproductive medicine and stem cell biology because TE cells have a greater developmental potential than assumed previously.
http://www.ncbi.nlm.nih.gov/m/.....65/related
Totipotency and lineage segregation in the human embryo.
Authors
De Paepe C, et al. Show all
Journal
Mol Hum Reprod. 2014 Jul;20(7):599-618. doi: 10.1093/molehr/gau027. Epub 2014 Apr 3.
Affiliation
Abstract
During human preimplantation development the totipotent zygote divides and undergoes a number of changes that lead to the first lineage differentiation in the blastocyst displaying trophectoderm (TE) and inner cell mass (ICM) on Day 5. The TE is a differentiated epithelium needed for implantation and the ICM forms the embryo proper and serves as a source for pluripotent embryonic stem cells (ESCs). The blastocyst implants around Day 7. The second lineage differentiation occurs in the ICM after implantation resulting in specification of primitive endoderm and epiblast. Knowledge on human preimplantation development is limited due to ethical and legal restrictions on embryo research and scarcity of materials. Studies in the human are mainly descriptive and lack functional evidence. Most information on embryo development is obtained from animal models and ESC cultures and should be extrapolated with caution. This paper reviews totipotency and the molecular determinants and pathways involved in lineage segregation in the human embryo, as well as the role of embryonic genome activation, cell cycle features and epigenetic modifications.
http://www.ncbi.nlm.nih.gov/m/.....11/related
Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo.
Authors
Schrode N, et al. Show all
Journal
Genesis. 2013 Apr;51(4):219-33. doi: 10.1002/dvg.22368. Epub 2013 Feb 25.
Affiliation
Abstract
The preimplantation period of mouse early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast. During this period two cell fate decisions are made while cells gradually lose their totipotency. The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper. Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo. Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed.
http://www.ncbi.nlm.nih.gov/m/pubmed/23349011/
Mitochondria: determinants of stem cell fate?
doi: 10.1089/scd.2009.1806.edi.
Stem cells are traditionally classified as being either embryonic stem cells (ESCs) or somatic stem cells. Such a designation has now become blurred by the advent of ostensibly pluripotent cells derived from somatic cells, referred to as induced pluripotent stem cells. Mitochondria are the membrane bound organelles that provide the majority of a cell’s chemical energy via their production of adenosine triphosphate. Mitochondria are also known to be vital components in many cell processes including differentiation and apoptosis. We are still remarkably uninformed of how mitochondrial function affects stem cell behavior. Reviewed evidence suggests that mitochondrial function and integrity affect stem cell viability, proliferative and differential potential, and lifespan. Mitochondrial status therefore has profound and as yet unexamined implications for the current drive to develop induced pluripotent stem cells as a therapeutic resource.
http://www.ncbi.nlm.nih.gov/m/pubmed/19563264/
Spatial organization within a niche as a determinant of stem-cell fate
Structure and activity investigations of the cell fate determinant, SpoIIE, from Bacillus subtitles
Follow-up to # 207
That is a simple system. How did we get it to begin with? How did it ‘evolve’ to more complex systems that work?
The Duration of T Cell Stimulation Is a Critical Determinant of Cell Fate and Plasticity
MicroRNAs as Neuronal Fate Determinants
Metabolic Determinants of Stem Cell Pluripotency and Cell Fate Commitments
microRNAs: key triggers of neuronal cell fate
Cell fate determinants as regulators of cancer metastasis
Control Systems of Membrane Transport at the Interface between the Endoplasmic Reticulum and the Golgi
High-Resolution Temporal Analysis Reveals a Functional Timeline for the Molecular Regulation of Cytokinesis
Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
RE: # 216
Would like to read GP’s comments on this.
The problem with “The Third Way” is that it is not really an alternative to Creationism/Evolution. It does not offer an explanation of origins, so much as hope to provide license to scientists to discuss how life actually functions without the need to fit it into an Evolutionary storyline. It’s an attempt to be able to say “I don’t know how it got that way” without being accused of being called a creationist because what they observe doesn’t fit the Darwinist fairy tale.
Basically, it’s an attempt to say “please don’t shoot me, I’m not a creationist” while releasing research and experimentation that doesn’t fit any current molecules-to-man storyline. I would call it more a parallel to ID (without the logical inference of “Design must be involved”) than Creationism/Evolution. ID is kind of “creation-friendly common descent”, while the Third Way is “evolution-friendly common descent”, where both have a healthy dose of “we don’t know”. Creationism/Evolution respond “yes we do”.
I think, Dionisio, that you will find not a lot of discussion on the Third Way until it makes assertions that go beyond “this is how biology works today”. When/If they come up with their own “Origin Myth” things will change.
drc466
I think I understood your explanation and see your point. Thank you for the comments.
Insights into the molecular mechanisms underlying diversified wing venation among insects
Insect wings are great resources for studying morphological diversities in nature as well as in fossil records. Among them, variation in wing venation is one of the most characteristic features of insect species. Venation is therefore, undeniably a key factor of species-specific functional traits of the wings; however, the mechanism underlying wing vein formation among insects largely remains unexplored. Our knowledge of the genetic basis of wing development is solely restricted to Drosophila melanogaster. A critical step in wing vein development in Drosophila is the activation of the decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signalling pathway during pupal stages. A key mechanism is the directional transport of Dpp from the longitudinal veins into the posterior crossvein by BMP-binding proteins, resulting in redistribution of Dpp that reflects wing vein patterns. Recent works on the sawfly Athalia rosae, of the order Hymenoptera, also suggested that the Dpp transport system is required to specify fore- and hindwing vein patterns. Given that Dpp redistribution via transport is likely to be a key mechanism for establishing wing vein patterns, this raises the interesting possibility that distinct wing vein patterns are generated, based on where Dpp is transported. Experimental evidence in Drosophila suggests that the direction of Dpp transport is regulated by prepatterned positional information. These observations lead to the postulation that Dpp generates diversified insect wing vein patterns through species-specific positional information of its directional transport. Extension of these observations in some winged insects will provide further insights into the mechanisms underlying diversified wing venation among insects.
doi: 10.1098/rspb.2014.0264
http://rspb.royalsocietypublis.....0fac0be6ef
7
A CENP-S/X complex assembles at the centromere in S and G2 phases of the human cell cycle
The functional identity of centromeres arises from a set of specific nucleoprotein particle subunits of the centromeric chromatin fibre. These include CENP-A and histone H3 nucleosomes and a novel nucleosome-like complex of CENPs -T, -W, -S and -X. Fluorescence cross-correlation spectroscopy and Förster resonance energy transfer (FRET) revealed that human CENP-S and -X exist principally in complex in soluble form and retain proximity when assembled at centromeres. Conditional labelling experiments show that they both assemble de novo during S phase and G2, increasing approximately three- to fourfold in abundance at centromeres. Fluorescence recovery after photobleaching (FRAP) measurements documented steady-state exchange between soluble and assembled pools, with CENP-X exchanging approximately 10 times faster than CENP-S (t1/2 ? 10 min versus 120 min). CENP-S binding to sites of DNA damage was quite distinct, with a FRAP half-time of approximately 160 s. Fluorescent two-hybrid analysis identified CENP-T as a uniquely strong CENP-S binding protein and this association was confirmed by FRET, revealing a centromere-bound complex containing CENP-S, CENP-X and CENP-T in proximity to histone H3 but not CENP-A. We propose that deposition of the CENP-T/W/S/X particle reveals a kinetochore-specific chromatin assembly pathway that functions to switch centromeric chromatin to a mitosis-competent state after DNA replication. Centromeres shuttle between CENP-A-rich, replication-competent and H3-CENP-T/W/S/X-rich mitosis-competent compositions in the cell cycle.
doi: 10.1098/rsob.130229
http://rsob.royalsocietypublis.....bc6e9ab40b
Epigenetic regulation of adult stem cell function
Understanding the cellular and molecular mechanisms that specify cell lineages throughout development, and that maintain tissue homeostasis during adulthood, is paramount towards our understanding of why we age or develop pathologies such as cancer. Epigenetic mechanisms ensure that genetically identical cells acquire different fates during embryonic development and are therefore essential for the proper progression of development. How they do so is still a matter of intense investigation, but there is sufficient evidence indicating that they act in a concerted manner with inductive signals and tissue-specific transcription factors to promote and stabilize fate changes along the three germ layers during development. In consequence, it is generally hypothesized that epigenetic mechanisms are also required for the continuous maintenance of cell fate during adulthood. However, in vivo models in which different epigenetic factors have been depleted in different tissues do not show overt changes in cell lineage, thus not strongly supporting this view. Instead, the function of some of these factors appears to be primarily associated with tissue functionality, and a strong causal relationship has been established between their misregulation and a diseased state. In this review, we summarize our current knowledge of the role of epigenetic factors in adult stem cell function and tissue homeostasis.
DOI: 10.1111/febs.12946
http://onlinelibrary.wiley.com.....6/abstract
Link Between DNA Damage and Centriole Disengagement/Reduplication in Untransformed Human Cells
The radiation and radiomimetic drugs used to treat human tumors damage DNA in both cancer cells and normal proliferating cells. Centrosome amplification after DNA damage is well established for transformed cell types but is sparsely reported and not fully understood in untransformed cells. We characterize centriole behavior after DNA damage in synchronized untransformed human cells. One hour treatment of S phase cells with the radiomimetic drug, Doxorubicin, prolongs G2 by at least 72?h, though 14% of the cells eventually go through mitosis in that time. By 72?h after DNA damage we observe a 52% incidence of centriole disengagement plus a 10% incidence of extra centrioles. We find that either APC/C or Plk activities can disengage centrioles after DNA damage, though they normally work in concert. All disengaged centrioles are associated with ?-tubulin and maturation markers and thus, should in principle be capable of reduplicating and organizing spindle poles. The low incidence of reduplication of disengaged centrioles during G2 is due to the p53-dependent expression of p21 and the consequent loss of Cdk2 activity. We find that 26% of the cells going through mitosis after DNA damage contain disengaged or extra centrioles. This could produce genomic instability through transient or persistent spindle multipolarity. Thus, for cancer patients the use of DNA damaging therapies raises the chances of genomic instability and evolution of transformed characteristics in proliferating normal cell populations. J. Cell. Physiol. 229: 1427–1436, 2014. © 2014 Wiley Periodicals, Inc.
DOI: 10.1002/jcp.24579
http://onlinelibrary.wiley.com.....9/abstract
Quantifying Mitotic Chromosome Dynamics and Positioning
The proper organization and segregation of chromosomes during cell division is essential to the preservation of genomic integrity. To understand the mechanisms that spatially control the arrangement and dynamics of mitotic chromosomes requires imaging assays to quantitatively resolve their positions and movements. Here, we will discuss analytical approaches to investigate the position-dependent control of mitotic chromosomes in cultured cells. These methods can be used to dissect the specific contributions of mitotic proteins to the molecular control of chromosome dynamics. J. Cell. Physiol. 229: 1301–1305, 2014. © 2014 Wiley Periodicals, Inc.
DOI: 10.1002/jcp.24634
http://onlinelibrary.wiley.com.....4/abstract
Kinetochore: Structure, Function and Evolution
Duplicated eukaryotic chromosomes are segregated into daughter cells through cell division. Faithful chromosome segregation depends on kinetochores, which are specialized macromolecular structures built upon centromeric chromatin. The dynamic kinetochore structures connect chromosomes with spindle microtubules, power chromosome movement, and signal the activation and silencing of the spindle assembly checkpoint (SAC). Molecular analyses of the components and architecture of kinetochores have advanced rapidly in recent years. A human kinetochore contains approximately 200 proteins, many of which are evolutionarily conserved in other organisms. A histone H3 variant, CENP-A and associated constitutive centromere proteins lay the foundation for kinetochore build-up. Multiple kinetochore-localised microtubule-binding proteins including the Ndc80 complex help regulate chromosome movement. The SAC signalling originates from kinetochores and contributes to the fidelity of chromosome segregation. Many fascinating properties remain to be elucidated about the kinetochore as a fundamental machinery to maintain genomic stability.
Key Concepts:
•Chromosome segregation in eukaryotic cells depends upon connecting spindle microtubules with special macromolecular structures on chromosomes called kinetochores.
•The centromere is the chromosomal locus where a kinetochore is built.
•Laying the foundation for kinetochore assembly at centromeres are CENP-A (a histone H3 variant) containing nucleosomes and a group of CENP-A associated proteins (termed constitutive centromere proteins).
•There are multiple microtubule motors and nonmotor microtubule-binding proteins localised at kinetochores to coordinate chromosome movement.
•A 10 protein complex called KMN network is currently thought to provide the primary end-on microtubule-binding activity.
•The spindle assembly checkpoint (SAC) monitors the kinetochore–microtubule attachment and signals the delay of the metaphase-to-anaphase transition when defects are detected.
•Conformational change of MAD2 and assembly of the mitotic checkpoint complex (MCC) are the key events to activate the SAC.
•Comparative studies of similar and distinct kinetochore composition, structure and function in different species and during mitosis or meiosis have provided evolutionary perspectives on mechanisms regulating chromosome segregation.
DOI: 10.1002/9780470015902.a0006237.pub2
http://onlinelibrary.wiley.com.....2/abstract
Human Embryonic Aneuploidy
Human embryonic aneuploidy can have a meiotic or a mitotic origin. The majority of meiotic chromosome errors arise during oogenesis. Two main aneuploidy-causing mechanisms have been defined: the first involves the nondisjunction of entire chromosomes and takes place during both meiotic divisions, whereas the second involves the premature division of a chromosome into its two sister chromatids during meiosis I, followed by their random segregation. Mitotic aneuploidy can arise as a consequence of problems such as nondisjunction, endoreduplication and anaphase lag and occurs most often during the first three divisions after fertilisation. The cleavage stage of development is characterised by the highest rates of aneuploidy, after which the incidence of cytogenetic abnormality decreases significantly. A large number of oocytes and embryos have been examined in order to define the spectrum of aneuploidies during the first few days of life and to shed light upon their origins. Various classical and molecular cytogenetic methods have been employed for this purpose, and valuable data of biological and clinical relevance have been obtained.
Key Concepts:
•Aneuploidy is the most important genetic cause of human reproductive wastage (i.e. the principal reason for embryo implantation failure and miscarriage).
•The outcome of assisted reproductive treatments (e.g. in vitro fertilisation (IVF)) and natural reproductive cycles is negatively affected by aneuploidy.
•Most meiotically derived abnormalities arise during oogenesis.
•There is a strong relationship between advancing female age and increasing aneuploidy rates in oocytes.
•Two distinct mechanisms of oocyte chromosome malsegregation have been described, whole chromosome nondisjunction and unbalanced chromatid predivision.
•Post-zygotic aneuploidy usually arises during the first few mitotic divisions and leads to mosaicism in the embryo.
•There are three main mechanisms responsible for aneuploidy of mitotic origin: anaphase lag, endoreduplication and mitotic nondisjunction.
•The cleavage stage of preimplantation development is associated with the highest aneuploidy rates.
•The frequency of chromosome abnormalities and mosaicism declines as embryos progress to the blastocyst stage, presumably due to loss of abnormal cells or demise of affected embryos.
DOI: 10.1002/9780470015902.a0025706
http://onlinelibrary.wiley.com.....6/abstract
Preparing a cell for nuclear envelope breakdown: Spatio-temporal control of phosphorylation during mitotic entry
Chromosome segregation requires the ordered separation of the newly replicated chromosomes between the two daughter cells. In most cells, this requires nuclear envelope (NE) disassembly during mitotic entry and its reformation at mitotic exit. Nuclear envelope breakdown (NEB) results in the mixture of two cellular compartments. This process is controlled through phosphorylation of multiple targets by cyclin-dependent kinase 1 (Cdk1)-cyclin B complexes as well as other mitotic enzymes. Experimental evidence also suggests that nucleo-cytoplasmic transport of critical cell cycle regulators such as Cdk1-cyclin B complexes or Greatwall, a kinase responsible for the inactivation of PP2A phosphatases, plays a major role in maintaining the boost of mitotic phosphorylation thus preventing the potential mitotic collapse derived from NEB. These data suggest the relevance of nucleo-cytoplasmic transport not only to communicate cytoplasmic and nuclear compartments during interphase, but also to prepare cells for the mixture of these two compartments during mitosis.
DOI: 10.1002/bies.201400040
http://onlinelibrary.wiley.com.....0/abstract
Sister chromatid cohesion, which depends on cohesin, is essential for the faithful segregation of replicated chromosomes
Sororin pre-mRNA splicing is required for proper sister chromatid cohesion in human cells
Here, we report that splicing complex Prp19 is essential for cohesion in both G2 and mitosis, and consequently for the proper progression of the cell through mitosis. Inactivation of splicing factors SF3a120 and U2AF65 induces similar cohesion defects to Prp19 complex inactivation. Our data indicate that these splicing factors are all required for the accumulation of cohesion factor Sororin, by facilitating the proper splicing of its pre-mRNA. Finally, we show that ectopic expression of Sororin corrects defective cohesion caused by Prp19 complex inactivation. We propose that the Prp19 complex and the splicing machinery contribute to the establishment of cohesion by promoting Sororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability.
DOI: 10.15252/embr.201438640
http://onlinelibrary.wiley.com.....0/abstract
Coffee or tea?
Caffeine stabilizes Cdc25 independently of Rad3 in Schizosaccharomyces pombe contributing to checkpoint override
Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both Schizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S.?pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S.?pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25.
DOI: 10.1111/mmi.12592
http://onlinelibrary.wiley.com.....12592/full
Nuclear pores set the speed limit for mitosis.
DOI: 10.1016/j.cell.2014.02.004
The spindle assembly checkpoint prevents separation of sister chromatids until each kinetochore is attached to the mitotic spindle. Rodriguez-Bravo et al. report that the nuclear pore complex scaffolds spindle assembly checkpoint signaling in interphase
The spindle assembly checkpoint works like a rheostat rather than a toggle switch.
DOI: 10.1038/ncb2855
The spindle assembly checkpoint (SAC) is essential in mammalian mitosis to ensure the equal segregation of sister chromatids. The SAC generates a mitotic checkpoint complex (MCC) to prevent the anaphase-promoting complex/cyclosome (APC/C) from targeting key mitotic regulators for destruction until all of the chromosomes have attached to the mitotic apparatus. A single unattached kinetochore can delay anaphase for several hours, but how it is able to block the APC/C throughout the cell is not understood. Present concepts of the SAC posit that either it exhibits an all-or-nothing response or there is a minimum threshold sufficient to block the APC/C (ref. ). Here, we have used gene targeting to measure SAC activity, and find that it does not have an all-or-nothing response. Instead, the strength of the SAC depends on the amount of MAD2 recruited to kinetochores and on the amount of MCC formed. Furthermore, we show that different drugs activate the SAC to different extents, which may be relevant to their efficacy in chemotherapy.
Kinetic framework of spindle assembly checkpoint signalling.
The mitotic spindle assembly checkpoint (SAC) delays anaphase onset until all chromosomes have attached to both spindle poles. Here, we investigated SAC signalling kinetics in response to acute detachment of individual chromosomes using laser microsurgery. Most detached chromosomes delayed anaphase until they had realigned to the metaphase plate. A substantial fraction of cells, however, entered anaphase in the presence of unaligned chromosomes. We identify two mechanisms by which cells can bypass the SAC: first, single unattached chromosomes inhibit the anaphase-promoting complex/cyclosome (APC/C) less efficiently than a full complement of unattached chromosomes; second, because of the relatively slow kinetics of re-imposing APC/C inhibition during metaphase, cells were unresponsive to chromosome detachment up to several minutes before anaphase onset. Our study defines when cells irreversibly commit to enter anaphase and shows that the SAC signal strength correlates with the number of unattached chromosomes. Detailed knowledge about SAC signalling kinetics is important for understanding the emergence of aneuploidy and the response of cancer cells to chemotherapeutics targeting the mitotic spindle.
doi: 10.1038/ncb2842
http://www.ncbi.nlm.nih.gov/pubmed/24096243
Dynein-dependent transport of spindle assembly checkpoint proteins off kinetochores toward spindle poles.
DOI: 10.1016/j.febslet.2014.07.011
A predominant mechanism of spindle assembly checkpoint (SAC) silencing is dynein-mediated transport of certain kinetochore proteins along microtubules. There are still conflicting data as to which SAC proteins are dynein cargoes. Using two ATP reduction assays, we found that the core SAC proteins Mad1, Mad2, Bub1, BubR1, and Bub3 redistributed from attached kinetochores to spindle poles, in a dynein-dependent manner. This redistribution still occurred in metaphase-arrested cells, at a time when the SAC should be satisfied and silenced. Unexpectedly, we found that a pool of Hec1 and Mis12 also relocalizes to spindle poles, suggesting KMN components as additional dynein cargoes. The potential significance of these results for SAC silencing is discussed.
The dynamic protein Knl1 – a kinetochore rendezvous
Journal of Cell Science (Impact Factor: 5.88). 07/2014; DOI: 10.13140/2.1.2196.2881
Knl1 (also known as CASC5, UniProt Q8NG31) is a scaffolding protein that is required for proper kinetochore assembly, spindle assembly checkpoint (SAC) function and chromosome congression.
A number of recent reports have confirmed the prominence of Knl1 in these processes and provided molecular details and structural features that dictate Knl1 functions in higher organisms.
Knl1 recruits SAC components to the kinetochore and is the substrate of certain protein kinases and phosphatases, the interplay of which ensures the exquisite regulation of the aforementioned processes.
In this Commentary, we discuss the overall domain organization of Knl1 and the roles of this protein as a versatile docking platform.
We present emerging roles of the protein interaction motifs present in Knl1, including the RVSF, SILK, MELT and KI motifs, and their role in the recruitment and regulation of the SAC proteins Bub1, BubR1, Bub3 and Aurora B.
Finally, we explore how the regions of low structural complexity that characterize Knl1 are implicated in the cooperative interactions that mediate binding partner recognition and scaffolding activity by Knl1
Here’s an important biological subsystem that the third way folks could try to research in order to explain its detailed origin.
At least now we know more about it than we knew not so long ago.
The Cep192-Organized Aurora A-Plk1 Cascade Is Essential for Centrosome Cycle and Bipolar Spindle Assembly
DOI: http://dx.doi.org/10.1016/j.molcel.2014.06.016
As cells enter mitosis, the two centrosomes separate and grow dramatically, each forming a nascent spindle pole that nucleates a radial array of microtubules. Centrosome growth (and associated microtubule nucleation surge), termed maturation, involves the recruitment of pericentriolar material components via an as-yet unknown mechanism. Here, we show that Cep192 binds Aurora A and Plk1, targets them to centrosomes in a pericentrin-dependent manner, and promotes sequential activation of both kinases via T-loop phosphorylation. The Cep192-bound Plk1 then phosphorylates Cep192 at several residues to generate the attachment sites for the ?-tubulin ring complex and, possibly, other pericentriolar material components, thus promoting their recruitment and subsequent microtubule nucleation. We further found that the Cep192-dependent Aurora A-Plk1 activity is essential for kinesin-5-mediated centrosome separation, bipolar spindle formation, and equal centrosome/centriole segregation into daughter cells. Thus, our study identifies a Cep192-organized signaling cascade that underlies both centrosome maturation and bipolar spindle assembly.
http://www.cell.com/molecular-.....ll%20Press
Systems approach to metabolic diseases
In order to develop a complete understanding of a biological system, information must cover multiple dimensions. Over the last ten years, we have witnessed decisive advances in bioinformatics, genome sequencing, and high-throughput technologies, that have highlighted the need for approaching biological systems as a whole. Metabolic diseases, including type 2 diabetes and cardiovascular disease, as well as cancer, involve complex genetic, molecular, and environmental interactions, and systems-based approaches have proven to be instrumental in tackling this complexity by integrating genomic, molecular, and physiological data.
This meeting will provide a unique opportunity to bring together experts in systems biology and metabolism to discuss how ‘Omics’ approaches can be exploited in an effort to understand the perturbations that take place in the pathogenesis of metabolic diseases. We will discuss novel approaches for studying metabolic alterations in a high-throughput scale and explore how epigenomics, non-coding RNAs, and environmental factors control metabolic pathways in disease settings.
Does this article leave some important questions unanswered and raise new questions?
Nature’s artistic and engineering skills are evident in proteins, life’s robust molecular machines.
For proteins, energy landscapes serve as maps that show the number of possible forms they may take as they fold.
http://www.rdmag.com/news/2014.....ame-forces
#238 Fascinating article – all sorts of imaginary, teleological processes at work. “Nature selects” the right things at the right time, “otherwise we wouldn’t be here”. Evolution is “guided” to solutions. That’s just the way evolution works. 🙂 Of course, if you question this, you’re wrong: “The only way to explain the funnel’s existence is to say that sequences are not random, but that they’re the result of evolution.”
Ok! I didn’t realize there was only one just-so story we could use to explain this. 🙂
[We know nature selected viable sequences because we’re here and therefore evolution works!]
[Fortunately, nature selects useful and stable proteins. The genius of evolution.]
[I’m glad we didn’t have to worry about mutations in order to understand how evolution works. That would have been far too messy. Instead, we know that nature selects all the right stuff — and it all happened to be there for selection, right when nature needed it.]
[Of course, energy guided evolution to be successful. We exist, therefore evolution was guided by energy to select us. It makes sense!]
[Evolution evolved them to avoid frustration so that they could become the best and most optimal organisms they could truly be. Otherwise, evolution would have failed in its task and that would have been bad. Good job, evolution!]
[The protein evolved to find positive solutions, otherwise, the organism would die and evolution would be very sad about that. But we do exist – so evolution must have worked very well indeed!]
[ “Proteins evolved through this process. If not, we wouldn’t be here.”
Got it! We exist, therefore we evolved. There’s no other answer to it. If it was random, there would be no guidance to the right solution. The wrong solution would be dead organisms and extinction. Thankfully, evolution would not stand for that – it insisted on guiding things to the right solution.]
[Right, because the proteins wanted to arrive at the right solution. Energy fields guided evolution so that it would create human beings.]
Silver Asiatic @ 239
Excellent detailed review of that article!
Thank you for the insightful comments!
RE: # 238
original papers:
http://www.pnas.org/content/ea.....1.abstract
http://news.rice.edu/2014/08/1.....me-forces/
Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31comet
vol. 111 no. 33
> Esther Eytan, 12019–12024,
doi: 10.1073/pnas.1412901111
The mitotic checkpoint system has an important role to ensure accurate segregation of chromosomes in mitosis. This system regulates the activity of the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) by the formation of a negatively acting Mitotic Checkpoint Complex (MCC). When the checkpoint is satisfied, MCC is disassembled, but the mechanisms of MCC disassembly are not well understood. We show here that the ATP-hydrolyzing enzyme Thyroid Receptor Interacting Protein 13 (TRIP13), along with the MCC-targeting protein p31comet, promote the disassembly of the mitotic checkpoint complexes and the inactivation of the mitotic checkpoint. The results reveal an important molecular mechanism in the regulation of APC/C by the mitotic checkpoint.
The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20. When the checkpoint signal is turned off, MCC is disassembled and the checkpoint is inactivated. The mechanisms of the disassembly of MCC are not sufficiently understood. We have previously observed that ATP hydrolysis is required for the action of the Mad2-binding protein p31comet to disassemble MCC. We now show that HeLa cell extracts contain a factor that promotes ATP- and p31comet-dependent disassembly of a Cdc20–Mad2 subcomplex and identify it as Thyroid Receptor Interacting Protein 13 (TRIP13), an AAA-ATPase known to interact with p31comet. The joint action of TRIP13 and p31comet also promotes the release of Mad2 from MCC, participates in the complete disassembly of MCC and abrogates checkpoint inhibition of APC/C. We propose that TRIP13 plays centrally important roles in the sequence of events leading to MCC disassembly and checkpoint inactivation.
http://www.pnas.org/content/11.....1aa0472954
Thanks, Dionisio. There were some great moments in that article. This is my favorite:
The way they concluded it wasn’t a random walk is “we wouldn’t be here” otherwise and there would be “no overall guidance to the right solution”.
It’s comical.
A whole conference dedicated mainly to protein folding issues, including chaperones.
https://secure.faseb.org/FASEB/meetings/summrconf/Programs/11617.pdf
Molecular high-speed origami: Researchers elucidate important mechanism of protein folding
http://phys.org/news/2014-05-m.....rtant.html
A better understanding of cell to cell communication
http://phys.org/news/2014-08-cell.html#nRlv
if polyphosphate worked well for protein folding, why did evolution fire it? Why did it hire a team of chaperones to do the work that polyphosphate was doing so well? How did it go from the polyphosphate to the chaperone network?
doesn’t NS follows the principle that “if ain’t broke, don’t fix it”?
any thoughts on this?
http://phys.org/news/2014-02-c.....lions.html
Molecular Chaperones in Cellular Protein Folding: The Birth of a Field
DOI: http://dx.doi.org/10.1016/j.cell.2014.03.029
The early decades of Cell witnessed key discoveries that coalesced into the field of chaperones, protein folding, and protein quality control.
Molecular Chaperone Functions in Protein Folding and Proteostasis
Annual Review of Biochemistry
Vol. 82: 323-355 (Volume publication date June 2013)
DOI: 10.1146/annurev-biochem-060208-092442
The biological functions of proteins are governed by their three-dimensional fold.
Protein folding, maintenance of proteome integrity, and protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones.
Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)folding. Folding occurs upon controlled release of newly synthesized proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
http://www.annualreviews.org/d.....208-092442
Orchestration of secretory protein folding by ER chaperones
doi: 10.1016/j.bbamcr.2013.03.007.
The endoplasmic reticulum is a major compartment of protein biogenesis in the cell, dedicated to production of secretory, membrane and organelle proteins. The secretome has distinct structural and post-translational characteristics, since folding in the ER occurs in an environment that is distinct in terms of its ionic composition, dynamics and requirements for quality control. The folding machinery in the ER therefore includes chaperones and folding enzymes that introduce, monitor and react to disulfide bonds, glycans, and fluctuations of luminal calcium. We describe the major chaperone networks in the lumen and discuss how they have distinct modes of operation that enable cells to accomplish highly efficient production of the secretome. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Copyright © 2013 Elsevier B.V. All rights reserved.
http://www.ncbi.nlm.nih.gov/pubmed/23507200
the emerging notion that this process may be more complex than previously appreciated.
DOI 10.15252/embj.201489490
Following fertilization, activation of a complex developmental program requires the differential expression of key genes. In most metazoa, the prevailing view is that early differential gene expression occurs primarily through post?transcriptional regulation of maternally deposited products in the oocyte. Two novel studies published from the Rajewsky laboratory in this issue of The EMBO Journal add significantly to the emerging notion that this process may be more complex than previously appreciated.
See also: M Stoeckius et al (August 2014a)
and M Stoeckius et al (August 2014b)
In the first study from Rajewsky and co?workers (Stoeckius et al, 2014a), global approaches including metabolic labeling and RNA?seq of 1?cell stage embryos are employed to discover significant deposition of mRNAs and small non?coding RNAs of paternal origin into Caenorhabditis elegans oocytes. In their second paper, the authors comprehensively surveyed transcriptome and proteome changes that occur at one of the earliest steps in animal development: the oocyte?to?embryo transition (OET).
The results thus establish a nearly complete inventory of one of the most fundamental transition periods in embryonic development.
The most prominent finding here is the discovery of a remarkable wave of mRNA turnover that immediately follows fertilization.
They go further to characterize an mRNA clearance mechanism involving a 3? UTR polyC motif that allows coordinated and rapid turnover of maternal mRNAs prior to what is generally considered to be the maternal?to?zygotic transition in C. elegans (Stoeckius et al, 2014b). Taken together, these rather unexpected results offer a glimpse into the role paternal RNAs might play during early developmental decisions.
http://emboj.embopress.org/content/33/16/1729
it is currently unclear how the precursors for most Piwi?interacting RNAs (piRNAs) are recognized as substrates by the piRNA processing machinery that resides in cytoplasmic granules called nuage.
Primary piRNA biogenesis: caught up in a Maelstrom
Radha Raman Pandey, Ramesh S Pillai
DOI 10.15252/embj.201489670 | Published online 22.08.2014
The EMBO Journal (2014) embj.201489670
Precursors for most Piwi?interacting RNAs (piRNAs) are indistinguishable from other RNA polymerase II?transcribed long non?coding RNAs. So, it is currently unclear how they are recognized as substrates by the piRNA processing machinery that resides in cytoplasmic granules called nuage. In this issue, Castaneda et al (2014) reveal a role for the nuage component and nucleo?cytoplasmic shuttling protein Maelstrom in mouse piRNA biogenesis.
See also: J Castaneda et al
Germ cells are entrusted with the task of faithfully transmitting genetic information from one generation to the next. A major threat to germline genome integrity is the activity of mobile genetic elements called transposons, as they have the potential to cause mutations, usually leading to infertility. To counteract this threat, animal germlines have evolved a conserved small RNA?based transposon defense system composed of Piwi proteins and their associated piRNAs (Malone & Hannon, 2009). In their simplest form, piRNAs guide Piwi endonucleases to cleave transposon transcripts resulting in their degradation. More complex systems come into play when nuclear Piwi proteins mediate transcriptional silencing of target transposon loci by recruitment of H3K9me3 chromatin marks and/or DNA methylation as in Drosophila and mice, respectively. While piRNAs targeting transposable elements is a universal feature across the animal kingdom, the mammalian male germline expresses an abundant set of piRNAs
http://emboj.embopress.org/con......201489670
MicroRNAs as Neuronal Fate Determinants
doi: 10.1177/1073858413497265
Since the discovery of short, regulatory microRNAs (miRNA) 20 years ago, the understanding of their impact on gene regulation has dramatically increased.
Differentiation of cells requires comprehensive changes in regulatory networks at all levels of gene expression.
Posttranscriptional regulation by miRNA leads to rapid modifications in the protein level of large gene networks, and it is therefore not surprising that miRNAs have been found to influence the fate of differentiating cells.
Several recent studies have shown that overexpression of a single miRNA in different cellular contexts results in forced differentiation of nerve cells.
Loss of this miRNA constrains neurogenesis and promotes gliogenesis.
This miRNA, miR-124, is probably the most well-documented example of a miRNA that controls nerve cell fate determination.
In this review we summarize the recent findings on miR-124, potential molecular mechanisms used by miR-124 to drive neuronal differentiation, and outline future directions.
http://nro.sagepub.com/content.....5.abstract
Metabolic Determinants of Stem Cell Pluripotency and Cell Fate Commitments
The metabolic needs of cells are determined by function and fate. Pluripotent cells must make the choice to either self-renew, or commit to alternative cell fates. What are the changes in metabolic programs and cell bioenergetics associated with this stem cell choice? Do cell fate decisions determine metabolic activity, or do metabolic switches trigger the commitment to alternative cell fates? How do rapidly proliferating cells signal their comprehensive needs for more ATP, reducing equivalents, and biosynthetic intermediates that provide for growth and division? Can small molecules be used to divert stem cells toward expansion of desired lineages for cell-based therapies? Speakers at this symposium will present their latest metabolomic findings on stem cell metabolism vs. lineage commitment — and how this knowledge may be applied for future therapies.
http://info.biotech-calendar.c.....ommitments
Piece of cake – very simple 😉
Planar Cell Polarity Goes Perpendicular
DOI: 10.1126/scisignal.2005416
Polarized distribution of signaling molecules followed by asymmetric cell division can restrict the distribution of cell fate determinants to a single daughter cell.
The larval skin of the frog is composed mostly of mucus-secreting goblet cells derived from the outer polarized epithelium of the embryonic ectoderm.
The skin also contains multiciliated cells, which are derived from a deeper layer of ventral ectoderm cells generated by occasional asymmetric divisions of the outer epithelial cells perpendicular to the epithelial plane. Huang et al. report that the Wnt receptor Lrp6 was enriched in the basolateral domain of the outer epithelial cells and uniformly present on the basal daughters after these cells divided asymmetrically. Wnt signaling through Lrp6 leads to nuclear accumulation of ?-catenin and activation of target genes. By endogenous and reporter gene expression criteria, basal cells showed greater Wnt signaling activity than outer epithelial cells. Inhibiting Wnt signaling reduced the number of ciliated cells, and injecting mRNA encoding ?-catenin promoted the differentiation of supernumerary multiciliated cells. Signaling through the Frizzled-planar cell polarity (Fz-PCP) pathway, which requires Wnt receptors of the Frizzled family, was required for the asymmetric distribution of Lrp6 in the epithelial cells. Dishevelled (Dvl), a multidomain protein involved in both Wnt-?-catenin and Fz-PCP signaling, colocalized with Lrp6 in the basolateral membrane of outer epithelial cells, and embryos lacking Dvl did not show polarized distribution of Lrp6. Polar localization of Lrp6 required domains in Dvl that mediate PCP signaling, but not a domain required only for Wnt-?-catenin signaling. Morpholino-mediated knockdown of Wnt5a, which has been implicated in PCP, or of Fz7 prevented the polarized distribution of both Lrp6 and Dvl in outer epithelial cells and enrichment of Lrp6 in deep cells. These findings indicate that PCP signaling can influence apicobasal polarity in addition to its well-established role in defining polarity within the plane of the epithelium and demonstrate that PCP and Wnt-?-catenin signaling can cooperate to link cell polarity to fate determination.
http://stke.sciencemag.org/con.....1.abstract
Cell Fate Decision
During each stem cell division, precise mechanisms insure that newly formed cells differentiate into the correct cell type that is required to maintain long-term homeostasis of their resident tissue.
http://www.urmc.rochester.edu/.....e_decision
mitotic spindle geometry and chromosome segregation
doi:10.1186/1747-1028-7-19
Assembly of a bipolar mitotic spindle is essential to ensure accurate chromosome segregation and prevent aneuploidy, and severe mitotic spindle defects are typically associated with cell death.
Recent studies have shown that mitotic spindles with initial geometric defects can undergo specific rearrangements so the cell can complete mitosis with a bipolar spindle and undergo bipolar chromosome segregation, thus preventing the risk of cell death associated with abnormal spindle structure.
Although this may appear as an advantageous strategy, transient defects in spindle geometry may be even more threatening to a cell population or organism than permanent spindle defects.
Indeed, transient spindle geometry defects cause high rates of chromosome mis-segregation and aneuploidy.
http://www.celldiv.com/content/7/1/19
A Gene Regulatory Network Controls the Binary Fate Decision of Rod and Bipolar Cells in the Vertebrate Retina
Gene regulatory networks (GRNs) regulate critical events during development. In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types. Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron. The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision. We identified a cis-regulatory module (CRM), B108, that mimics Blimp1 expression. Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1. Otx2 and ROR? were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.018
Making connections: interorganelle contacts orchestrate mitochondrial behavior
DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.004
Mitochondria are highly dynamic organelles.
During their life cycle they frequently fuse and divide, and damaged mitochondria are removed by autophagic degradation.
These processes serve to maintain mitochondrial function and ensure optimal energy supply for the cell.
It has recently become clear that this complex mitochondrial behavior is governed to a large extent by interactions with other organelles.
In this review, we describe mitochondrial contacts with the endoplasmic reticulum (ER), plasma membrane, and peroxisomes.
In particular, we highlight how mitochondrial fission, distribution, inheritance, and turnover are orchestrated by inter-organellar contacts in yeast and metazoa.
These interactions are pivotal for the integration of the dynamic mitochondrial network into the architecture of eukaryotic cells.
http://www.cell.com/trends/cel.....14)00065-8
How pervasive are circadian oscillations?
DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.005
Circadian oscillations play a critical role in coordinating the physiology, homeostasis, and behavior of biological systems.
Once thought to only be controlled by a master clock, recent high-throughput experiments suggest many genes and metabolites in a cell are potentially capable of circadian oscillations.
Each cell can reprogram itself and select a relatively small fraction of this broad repertoire for circadian oscillations, as a result of genetic, environmental, and even diet changes.
http://www.cell.com/trends/cel.....14)00069-5
Surviving change: the metabolic journey of hematopoietic stem cells
DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.001
Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that maintain blood production and are uniquely wired to adapt to diverse cellular fates during the lifetime of an organism.
Recent studies have highlighted a central role for metabolic plasticity in facilitating cell fate transitions and in preserving HSC functionality and survival.
This review summarizes our current understanding of the metabolic programs associated with HSC quiescence, self-renewal, and lineage commitment, and highlights the mechanistic underpinnings of these changing bioenergetics programs.
It also discusses the therapeutic potential of targeting metabolic drivers in the context of blood malignancies.
http://www.cell.com/trends/cel.....14)00062-2
Less well understood?
A CULLINary ride across the secretory pathway: more than just secretion
Mulitmeric cullin-RING ubiquitin ligases (CRLs) represent the largest class of ubiquitin ligases in eukaryotes.
However, most CRL ubiquitylation pathways remain uncharacterized.
CRLs control a myriad of functions by catalyzing mono- or poly-ubiquitylation of target proteins.
Recently, novel CRLs have been identified along the secretory pathway where they modify substrates involved in diverse cellular processes such as vesicle coat assembly and cell cycle progression.
This review discusses our current understanding of CRL ubiquitylation within the secretory pathway, with special emphasis on the emerging role of the Golgi as a ubiquitylation platform.
CRLs are also implicated in endosome function, where their specific roles are less well understood.
DOI: http://dx.doi.org/10.1016/j.tcb.2014.02.001
Communicating by touch – neurons are not alone
DOI: http://dx.doi.org/10.1016/j.tcb.2014.01.003
Long-distance cell–cell communication is essential for organ development and function.
Whereas neurons communicate at long distances by transferring signals at sites of direct contact (i.e., at synapses), it has been presumed that the only way other cell types signal is by dispersing signals through extracellular fluid – indirectly.
Recent evidence from Drosophila suggests that non-neuronal cells also exchange signaling proteins at sites of direct contact, even when long distances separate the cells.
We review here contact-mediated signaling in neurons and discuss how this signaling mechanism is shared by other cell types.
regulated expression of certain genes during differentiation of some cell types ?
[…]
Cellular and molecular longevity pathways: the old and the new
DOI: http://dx.doi.org/10.1016/j.tem.2013.12.003
Human lifespan has been increasing steadily during modern times, mainly due to medical advancements that combat infant mortality and various life-threatening diseases.
However, this gratifying longevity rise is accompanied by growing incidences of devastating age-related pathologies.
Understanding the cellular and molecular mechanisms that underlie aging and regulate longevity is of utmost relevance towards offsetting the impact of age-associated disorders and increasing the quality of life for the elderly.
Several evolutionarily conserved pathways that modulate lifespan have been identified in organisms ranging from yeast to primates.
Here we survey recent findings highlighting the interplay of various genetic, epigenetic, and cell-specific factors, and also symbiotic relationships, as longevity determinants.
We further discuss outstanding matters within the framework of emerging, integrative views of aging.
NuMA interacts with phosphoinositides and links the mitotic spindle with the plasma membrane
The positioning and the elongation of the mitotic spindle must be carefully regulated.
In human cells, the evolutionary conserved proteins LGN/G?i1?3 anchor the coiled?coil protein NuMA and dynein to the cell cortex during metaphase, thus ensuring proper spindle positioning.
The mechanisms governing cortical localization of NuMA and dynein during anaphase remain more elusive.
Here, we report that LGN/G?i1?3 are dispensable for NuMA?dependent cortical dynein enrichment during anaphase.
We further establish that NuMA is excluded from the equatorial region of the cell cortex in a manner that depends on the centralspindlin components CYK4 and MKLP1.
Importantly, we reveal that NuMA can directly associate with PtdInsP (PIP) and PtdInsP2 (PIP2) phosphoinositides in vitro.
Furthermore, chemical or enzymatic depletion of PIP/PIP2 prevents NuMA cortical localization during mitosis, and conversely, increasing PIP2 levels augments mitotic cortical NuMA.
Overall, our study uncovers a novel function for plasma membrane phospholipids in governing cortical NuMA distribution and thus the proper execution of mitosis.
DOI 10.15252/embj.201488147 | Published online 04.07.2014
The EMBO Journal (2014) 33, 1815-1830
http://emboj.embopress.org/content/33/16/1815
Supergenomic Network Compression
DOI: http://dx.doi.org/10.1016/j.cell.2014.07.011
A central problem in biology is to identify gene function.
One approach is to infer function in large supergenomic networks of interactivos and ancestral relationships among genes; however, their analysis can be computationally prohibitive.
We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships, and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks.
Compression enables global network analysis to computationally harness hundreds of interconnected genomes and to produce functional predictions.
As a demonstration, we show that the essential, but functionally uncharacterized Plasmodium falciparum antigen EXP1 is a membrane glutathione S-transferase.
EXP1 efficiently degrades cytotoxic hematin, is potently inhibited by artesunate, and is associated with artesunate metabolism and susceptibility in drug-pressured malaria parasites.
These data implicate EXP1 in the mode of action of a frontline antimalarial drug.
Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis
DOI: http://dx.doi.org/10.1016/j.stem.2014.07.005
In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations.
From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps.
DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci.
Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs.
We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells.
This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy.
Mad1 contribution to spindle assembly checkpoint signalling goes beyond presenting Mad2 at kinetochores
DOI 10.1002/embr.201338114
The spindle assembly checkpoint inhibits anaphase until all chromosomes have become attached to the mitotic spindle.
A complex between the checkpoint proteins Mad1 and Mad2 provides a platform for Mad2:Mad2 dimerization at unattached kinetochores, which enables Mad2 to delay anaphase.
Here, we show that mutations in Bub1 and within the Mad1 C?terminal domain impair the kinetochore localization of Mad1:Mad2 and abrogate checkpoint activity.
Artificial kinetochore recruitment of Mad1 in these mutants co?recruits Mad2; however, the checkpoint remains non?functional.
We identify specific mutations within the C?terminal head of Mad1 that impair checkpoint activity without affecting the kinetochore localization of Bub1, Mad1 or Mad2.
Hence, Mad1 potentially in conjunction with Bub1 has a crucial role in checkpoint signalling in addition to presenting Mad2.
http://embor.embopress.org/con......201338114
The Spindle Assembly Checkpoint Mechanism and the Consequences of its Dysfunction
Reviews the elegant design of the mitotic spindle assembly checkpoint pathway, the molecular processes that minimize the risks of improper chromosome segregation during cell division as a consequence of improper microtubule-kinetochore attachment.
https://html2-f.scribdassets.com/s1di7nr5s381su8/images/1-05dd0f6fed.jpg
Monitoring Spindle-Kinetochore Attachment
The precise mechanism by which the spindle checkpoint system detects improper chromatid bi-orientation has not been fully elucidated.
http://www.scribd.com/doc/1906.....ysfunction
The Cell’s Surveillance System: Introducing the Cell Cycle Checkpoint Pathways
The checkpoint pathways can be thought of as the cell’s surveillance systems that function to arrest cell cycle progression in response to detected problems in cell division or chromosome replication.
Checkpoint pathways ensure that DNA replication does not commence before all of the components necessary for its completion have been produced.
They also ensure that the replication process is not derailed by damaged DNA; that cells do not attempt to divide before genome duplication is complete; and that each daughter cell receives a complete set of chromosomes. Checkpoint pathways are essential for an organism’s viability.
Although a cell can complete its cycle successfully without them, their absence results in infidelity of chromosome transmission and a greatly raised susceptibility to DNA-damaging agents.
The consequence of checkpoint pathway inactivation is genome instability, which inevitably leads to cancer…
http://www.evolutionnews.org/2.....75151.html
Defining pathways of spindle checkpoint silencing: functional redundancy between Cdc20 ubiquitination and p31comet
A general molecular framework for spindle checkpoint inactivation is lacking. The Mad2 inhibitor, p31comet, has roles independent of the ubiquitin-proteasome pathway. This key finding allows the delineation of two partially redundant pathways for mitotic exit.
http://biblioteca.universia.ne.....89039.html
The spindle checkpoint
Every mitosis, replicated chromosomes must be accurately segregated into each daughter cell.
Pairs of sister chromatids attach to the bipolar mitotic spindle during prometaphase, they are aligned at metaphase, then sisters separate and are pulled to opposite poles during anaphase.
Failure to attach correctly to the spindle before anaphase onset results in unequal segregation of chromosomes, which can lead to cell death or disease.
The spindle checkpoint is a surveillance mechanism that delays anaphase onset until all chromosomes are correctly attached in a bipolar fashion to the mitotic spindle.
The core spindle checkpoint proteins are Mad1, Mad2, BubR1 (Mad3 in yeast), Bub1, Bub3 and Mps1. The Mad and Bub proteins were first identified in budding yeast by genetic screens for mutants that failed to arrest in mitosis when the spindle was destroyed (Taylor et al., 2004).
These proteins are conserved in all eukaryotes.
Several other checkpoint components, such as Rod, Zw10 and CENP-E, have since been identified in higher eukaryotes but have no yeast orthologues (Karess, 2005; Mao et al., 2003).
This reflects a more complex checkpoint regulation in higher eukaryotes where, unlike in yeasts, checkpoint proteins are essential and regulate normal mitotic timing (Meraldi et al., 2004; Taylor et al., 2004).
Here, we highlight current understanding of how the spindle checkpoint is activated, how it delays anaphase onset, and how it is silenced.
doi: 10.1242/?jcs.03165
http://jcs.biologists.org/content/119/20/4139.full
The spindle checkpoint.
DOI: 10.1016/S0959-437X(99)80010-0
Prior to sister-chromatid separation, the spindle checkpoint inhibits cell-cycle progression in response to a signal generated by mitotic spindle damage or by chromosomes that have not attached to microtubules.
Recent work has shown that the spindle checkpoint inhibits cell-cycle progression by direct binding of components of the spindle checkpoint pathway to components of a specialized ubiquitin-conjugating system that is responsible for triggering sister-chromatid separation.
http://www.researchgate.net/pu.....checkpoint
CK1 is required for a mitotic checkpoint that delays cytokinesis
Failure to accurately partition genetic material during cell division causes aneuploidy and drives tumorigenesis. Cell-cycle checkpoints safeguard cells from such catastrophes by impeding cell-cycle progression when mistakes arise.
FHA-RING E3 ligases, including human RNF8 and CHFR and fission yeast Dma1, relay checkpoint signals by binding phosphorylated proteins via their FHA domains and promoting ubiquitination of downstream targets.
Upon mitotic checkpoint activation, S. pombe Dma1 concentrates at spindle pole bodies (SPBs) in an FHA-dependent manner and ubiquitinates Sid4, a scaffold of Polo kinase, to suspend cytokinesis.
However, the kinase or kinases that phosphoprime Sid4 for Dma1-mediated ubiquitination are unknown.
Here, we report that the highly conserved protein kinase CK1 transmits the signal necessary to stall cytokinesis by phosphopriming Sid4 for Dma1-mediated ubiquitination.
Like Dma1, CK1 accumulates at SPBs during a mitotic arrest and associates stably with SPB components, including Sid4.
Our results establish CK1 as an integral component of a mitotic, ubiquitin-mediated checkpoint pathway.
doi: 10.1016/j.cub.2013.07.077.
http://www.ncbi.nlm.nih.gov/pubmed/24055157
BioMed Research International
Volume 2014 (2014), Article ID 145289, 8 pages
http://dx.doi.org/10.1155/2014/145289
An Overview of the Spindle Assembly Checkpoint Status
Abnormal chromosome number, or aneuploidy, is a common feature of human solid tumors, including oral cancer.
Deregulated spindle assembly checkpoint (SAC) is thought as one of the mechanisms that drive aneuploidy.
In normal cells, SAC prevents anaphase onset until all chromosomes are correctly aligned at the metaphase plate thereby ensuring genomic stability. Significantly, the activity of this checkpoint is compromised in many cancers.
While mutations are rather rare, many tumors show altered expression levels of SAC components.
Genomic alterations such as aneuploidy indicate a high risk of oral cancer and cancer-related mortality, and the molecular basis of these alterations is largely unknown.
Yet, our knowledge on the status of SAC components in oral cancer remains sparse.
In this review, we address the state of our knowledge regarding the SAC defects and the underlying molecular mechanisms in oral cancer, and discuss their therapeutic relevance, focusing our analysis on the core components of SAC and its target Cdc20.
http://www.hindawi.com/journals/bmri/2014/145289/
Cell cycle, checkpoints and cancer
Maintenance of genomic integrity is a pre-requisite for a safe and long lasting life and prevents development of diseases associated with genomic instability such as cancer.
DNA is constantly subjected and damaged by a large variety of chemical and physical agents, thus cells had to set up a number of surveillance mechanisms that constantly monitor the DNA integrity and the cell cycle progression and in the presence of any type of DNA damage activate pathways that lead to cell cycle checkpoints, DNA repair, apoptosis and transcription.
In recent years checkpoint pathways have been elucidated as an integral part of the DNA damage response and in fact dysfunctions or mutations of these pathways are important in the pathogenesis of malignant tumors.
Understanding the molecular mechanisms regulating the cell cycle progression and checkpoints and how these processes are altered in malignant cells may be crucial to better define the events behind such a complex and devastating desease like cancer…
http://atlasgeneticsoncology.o.....20123.html
Molecular pathways regulating mitotic spindle orientation in animal cells.
doi: 10.1242/dev.087627.
Orientation of the cell division axis is essential for the correct development and maintenance of tissue morphology, both for symmetric cell divisions and for the asymmetric distribution of fate determinants during, for example, stem cell divisions.
Oriented cell division depends on the positioning of the mitotic spindle relative to an axis of polarity+.
Recent studies have illuminated an expanding list of spindle orientation regulators, and a molecular model for how cells couple cortical polarity with spindle positioning has begun to emerge.
Here, we review both the well-established spindle orientation pathways and recently identified regulators, focusing on how communication between the cell cortex and the spindle is achieved, to provide a contemporary view of how positioning of the mitotic spindle occurs.
http://www.ncbi.nlm.nih.gov/pubmed/23571210
Oriented divisions, fate decisions.
doi: 10.1016/j.ceb.2013.08.003.
During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction.
Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis.
Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively.
The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices.
http://www.ncbi.nlm.nih.gov/pubmed/24021274
Spindle orientation and epidermal morphogenesis.
doi: 10.1098/rstb.2013.0016.
Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stem cells.
ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur.
During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane.
These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions.
That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells.
Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis.
http://www.ncbi.nlm.nih.gov/pubmed/24062586
Epithelial polarity and spindle orientation: intersecting pathways.
doi: 10.1098/rstb.2013.0291.
During asymmetric stem cell divisions, the mitotic spindle must be correctly oriented and positioned with respect to the axis of cell polarity to ensure that cell fate determinants are appropriately segregated into only one daughter cell.
By contrast, epithelial cells divide symmetrically and orient their mitotic spindles perpendicular to the main apical-basal polarity axis, so that both daughter cells remain within the epithelium.
Work in the past 20 years has defined a core ternary complex consisting of Pins, Mud and G?i that participates in spindle orientation in both asymmetric and symmetric divisions.
As additional factors that interact with this complex continue to be identified, a theme has emerged: there is substantial overlap between the mechanisms that orient the spindle and those that establish and maintain apical-basal polarity in epithelial cells.
In this review, we examine several factors implicated in both processes, namely Canoe, Bazooka, aPKC and Discs large, and consider the implications of this work on how the spindle is oriented during epithelial cell divisions.
http://www.ncbi.nlm.nih.gov/pubmed/24062590
Molecular mechanisms in spindle positioning: structures and new concepts.
doi: 10.1016/j.ceb.2012.10.005.
Coordination of cell cleavage with respect to cell geometry, cell polarity and neighboring tissues is critical for tissue maintenance, malignant transformation and metastasis.
The position of the mitotic spindle within the cell determines where cell cleavage occurs.
Spindle positioning is often mediated through capture of astral microtubules by motor proteins at the cell cortex.
Recently, the core dynein anchor complex has been structurally resolved.
Junctional complexes were shown to provide additional capture sites for astral microtubules in proliferating tissues.
Finally, latest studies show that signals from centrosomes control spindle positioning and propose novel concepts for generation of centrosome identity.
http://www.ncbi.nlm.nih.gov/pubmed/23142476
Mechanisms of spindle positioning.
doi: 10.1083/jcb.201210007
Accurate positioning of spindles is essential for asymmetric mitotic and meiotic cell divisions that are crucial for animal development and oocyte maturation, respectively.
The predominant model for spindle positioning, termed “cortical pulling,” involves attachment of the microtubule-based motor cytoplasmic dynein to the cortex, where it exerts a pulling force on microtubules that extend from the spindle poles to the cell cortex, thereby displacing the spindle.
Recent studies have addressed important details of the cortical pulling mechanism and have revealed alternative mechanisms that may be used when microtubules do not extend from the spindle to the cortex.
http://www.ncbi.nlm.nih.gov/pubmed/23337115
Need for multi-scale systems to identify spindle orientation regulators
doi: 10.3389/fphys.2014.00278
http://www.ncbi.nlm.nih.gov/pm.....MC4110440/
During cell division, the mitotic spindle captures chromosomes and segregates them into two equal sets.
The orientation and position of the mitotic spindle is important because the spindle equator becomes the plane of cell division.
For instance, in a columnar cell with apical and basal polarity, if the spindle pole-to-pole axis orients along the cell’s long axis, the cell will divide along its short-axis; however, if the spindle axis orients along the cell’s short axis, the cell will divide along its long-axis (Figure ?(Figure1A).1A).
Similarly when the spindle is off-centered (mis-positioned), it results in asymmetric cell sizes in the two daughter cells, which is often used to control tissue organization (Figure ?(Figure1B).1B).
Thus, errors in the orientation and positioning of the mitotic spindle can cause incorrect plane of cell division leading to incorrect cell size, content and neighborhood of daughter cells (Figures 1A,B).
Figure 1
http://www.ncbi.nlm.nih.gov/co.....-g0001.jpg
(A,B) Fates of incorrect spindle orientation and positioning: Cartoons show mitotic spindle movements relative to the substratum leading to spindle mis-orientation (A) and mis-positioning (B) with cortical bands highlighting polarity differences. In (A), misorientation alters the relative positions and contents of daughter cells, without affecting progenitor cell sizes. In (B), mispositioning affects daughter cell size, relative positions and their contents. Legend describing cell substratum, spindle microtubules, metaphase plate, and spindle movements included. (C) Oncogenic pathways implicated in spindle orientation: The Hippo, PTEN-PI3K, and Wnt tumor suppressor pathway components are marked in pink, blue, and purple, respectively. The oncogenic estrogen receptor (ER) pathway is marked in green. Together, these pathways regulate astral microtubule (marked in bold) function. Red arrows indicate force generation events. The Hippo pathway also influences transcriptional regulation of several genes involved in orientation (marked on chromosomes).
CYLD regulates spindle orientation by stabilizing astral microtubules and promoting dishevelled-NuMA-dynein/dynactin complex formation.
doi: 10.1073/pnas.1319341111
Oriented cell division is critical for cell fate specification, tissue organization, and tissue homeostasis, and relies on proper orientation of the mitotic spindle.
The molecular mechanisms underlying the regulation of spindle orientation remain largely unknown.
Herein, we identify a critical role for cylindromatosis (CYLD), a deubiquitinase and regulator of microtubule dynamics, in the control of spindle orientation.
CYLD is highly expressed in mitosis and promotes spindle orientation by stabilizing astral microtubules and deubiquitinating the cortical polarity protein dishevelled.
The deubiquitination of dishevelled enhances its interaction with nuclear mitotic apparatus, stimulating the cortical localization of nuclear mitotic apparatus and the dynein/dynactin motor complex, a requirement for generating pulling forces on astral microtubules.
These findings uncover CYLD as an important player in the orientation of the mitotic spindle and cell division and have important implications in health and disease.
http://www.ncbi.nlm.nih.gov/pubmed/24469800
Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis.
doi: 10.1242/dev.098731
Hox genes are classically ascribed to function in patterning the anterior-posterior axis of bilaterian animals; however, their role in directing molecular mechanisms underlying morphogenesis at the cellular level remains largely unstudied.
We unveil a non-classical role for the zebrafish hoxb1b gene, which shares ancestral functions with mammalian Hoxa1, in controlling progenitor cell shape and oriented cell division during zebrafish anterior hindbrain neural tube morphogenesis.
This is likely distinct from its role in cell fate acquisition and segment boundary formation.
We show that, without affecting major components of apico-basal or planar cell polarity, Hoxb1b regulates mitotic spindle rotation during the oriented neural keel symmetric mitoses that are required for normal neural tube lumen formation in the zebrafish.
This function correlates with a non-cell-autonomous requirement for Hoxb1b in regulating microtubule plus-end dynamics in progenitor cells in interphase.
We propose that Hox genes can influence global tissue morphogenesis by control of microtubule dynamics in individual cells in vivo.
http://www.ncbi.nlm.nih.gov/pubmed/24449840
Dionisio #286,
What controls the Hox genes? And what controls the controllers of Hox genes? And …
Dionisio, are they looking for the master-controller? What would that look like? Is such a thing even conceivable?
Box:
It’s a big problem. I have been trying to understand what is known (and, as you can see from Dionisio’s many references, it’s really a lot), and I am preparing an OP about that. I can certainly anticipate that what you call “the master-controller” (that I would call the “high level procedural information) remains really elusive.
As you know, our neo darwinist friends simply avoid the problem of the “master-controller”. They are satisfied with detailing the (apparently endless) complexities of the low-level procedures. Probably, they simply believe that all goes well because of some great, great, great luck!
Or, as Piotr said some time ago, “it’s just the memory of what worked”.
A very good memory indeed…
So he wants us to imagine something like a hard drive, with no means of memory storage, only retrieval, where random changes to the bit values on the drive result in a functioning computer with ever more complex features becoming available.
And we call this “the memory of what worked.”
How does it know what worked and what didn’t?
Gpuccio,
I’m looking very much forward to your OP on this subject. I’m a big fan of your writings. Though I wonder if “high level procedural information” can fulfill the role of “master-controller”. Does information possess decision power? Or, to use Mung’s analogy, can a hard drive control a computer?
Also, can a hard drive solve new problems – and in effect create new information?
Box:
Good questions.
I would say that information in a non conscious system, like a computer, possesses decision power for those decisions that have been programmed in the system. That can include situations that were not completely programmed, but that can be dealt in some way by the existing programs. That can even include “learning” (not in a conscious way, obviously). For example, neural networks and similar software can “learn” from inputs and from its elaboration of inputs, but only according to procedures that have been programmed in the original software.
Now, biological information is more similar to a working computer than to a hard drive. This is one of the points that I will try to discuss in my OP. In that sense, it can certainly take “decisions” about many things, which have been in some way (that still eludes us) programmed in it.
But you ask: can it “create new information”?
There are two aspects to that.
a) As you probably know, I firmly believe that a non conscious computing system can never “create new information” in the sense of new original dFSCI. IOWs it cannot define a new function and generate complex information to implement that function. As I have said, even systems that “learn” can only learn according to the rules for which they have pre-set definitions. A computing system has no idea of what a function is, because it has no idea of purpose. Therefore, it can never define a really new function, or even simply recognize it, unless it has been in some indirect way already defined in the system. So, lacking the definition of a new function, it cannot certainly compute complexity to implement it.
So, in this sense, even the biological information which we find “written” in cells (and which can be compared to a very complex computing system, must share this limitation. That’s why new proteins, or body plans, or regulatory networks are proof of a design intervention from outside, and cannot be explained simply as adaptations.
b) But I think that you suggest that some processes in the existing beings, different from the evolution of a new species, could be beyond the possibilities of a computational system, however complex. You quote tissue damage repair as an example.
Well, if it were true that some of the physiological processes in living beings cannot be explained by computational processes alone, that would mean that some other components (not completely physical and computational) are at work in living beings.
IOWs, that would correspond to proposing some form of what I would call “neo-vitalism”.
Now, I have nothing against that. Frankly, I am often tempted by that perspective. However, before I am labeled by our kind adversaries, at their fascinating sites, as a neo vitalist, with all the inevitable compliments that you can imagine, I must state that I have no explicit scientific arguments, at present, so I am not endorsing the idea as an explicit scientific theory.
However, if you are interested in creating a neo vitalism fan club, we can discuss! 🙂
Gpuccio, thank you very much for explaining your position.
Mysterious indeed. There are many examples for context-dependent behaviour of parts of organisms (e.g. mouse hair follicles in Talbott’s article). If this is to be explained by “high level procedural information” [HLPI], one has to wonder where HLPI resides. HLPI must be present at multiple levels. Chimerism is IMHO, among other phenomena, strong indication that there is even an abundance of HLPI residing at the level of the whole organism. What medium does HLPI use?
Box,
gpuccio has responded your good questions much better than I could have done it.
The more questions get answered, the clearer the big picture turns, revealing an elaborate information processing system that the best management information systems analysts in the world would drool at the sight of such marvel. Mind-boggling orchestrated choreographies that would make the ballets Swan Lake and The Nutcracker look like bad TV commercials.
There’s a problem: as outstanding questions get answered, newer questions are posed. Many things remain stubbornly elusive.
Now, and this is very important, we must remind ourselves that all that stuff is the result of the powerful magic ‘n-D e’ formula RV+NS+T and maybe -as gpuccio suggested- some great, great, great luck! 😉
Box,
I assume that in post #292 the concept “information in a non conscious system, like a computer,…” includes the operating system, drivers, app programs, as well as the engineering design that lead to the hardware where the software operates.
#295 correction
Box,
I assume that in post #292 the concept “information in a non conscious system, like a computer,…” includes the microprocessor signaling codes, the operating system, the drivers, the DBMS, the app programs, as well as the engineering design that lead to the hardware where the software operates and the technical specs that preceded all the software development and implementation.
Protein Clouds Gather and Disperse, But Why?
Blobs. Clouds. Assemblages. All these terms have been applied to poorly defined protein clusters that mysteriously form inside cells and then just as mysteriously disappear. These protein collections might be considered fuzzy outliers. After all, they defy the usual expectations for proteins. Proteins are supposed to assume definite structures that confer highly specific activities. Proteins—we like to think—work with each other and their nonprotein partners in lock-and-key fashion.
http://www.genengnews.com/gen-...../81250296/
Nucleic Acid Rain?
Nature’s design principles?
http://wyss.harvard.edu/viewpage/about-us/about-us
Mung
Did you mean “amino acid” clouds?
http://ghr.nlm.nih.gov/handboo.....rk/protein
Science research can use all available help, including computing resources for big data processing, modeling, simulations, analysis, documentation, organization.
Microsoft Biology Initiative
http://research.microsoft.com/.....fault.aspx
Advances in high throughput and platform technologies in biology present an unprecedented challenge in scale, management, and analysis of biological data.
Advances in computing architecture and scale are enabling simulations of complex biological processes at various organizational levels from atomic to cellular and beyond.
http://researcher.watson.ibm.c.....hp?id=1080
gpuccio,
check this conference, which is scheduled to start this week in the UK: The Dynamic Cell
Molecular Control of Chromosome Segregation
Cargo Sorting in the Endocytic Pathway
In-Vitro Analysis of Molecular Motors
Membrane Dynamics during Cytokinesis
Cell Migration and the Cytoskeleton
Cargo Sorting in the Secretory Pathway
#303 follow-up
that conference seems really loaded with very juicy material! I’m drooling already 🙂
All their papers must be up to date, with the latest and greatest info on the subjects, right?
Let’s keep an eye on this.
🙂
Separate to operate: control of centrosome positioning and separation
The centrosome is the main microtubule (MT)-organizing centre of animal cells.
It consists of two centrioles and a multi-layered proteinaceous structure that surrounds the centrioles, the so-called pericentriolar material.
Centrosomes promote de novo assembly of MTs and thus play important roles in Golgi organization, cell polarity, cell motility and the organization of the mitotic spindle.
To execute these functions, centrosomes have to adopt particular cellular positions.
Actin and MT networks and the association of the centrosomes to the nuclear envelope define the correct positioning of the centrosomes.
Another important feature of centrosomes is the centrosomal linker that connects the two centrosomes.
The centrosome linker assembles in late mitosis/G1 simultaneously with centriole disengagement and is dissolved before or at the beginning of mitosis.
Linker dissolution is important for mitotic spindle formation, and its cell cycle timing has profound influences on the execution of mitosis and proficiency of chromosome segregation.
In this review, we will focus on the mechanisms of centrosome positioning and separation, and describe their functions and mechanisms in the light of recent findings.
doi: 10.1098/rstb.2013.0461
http://rstb.royalsocietypublis.....1.abstract
OT
Big data should get much bigger – the info avalanche coming from research keeps increasing:
As next generation sequencing (NGS) platforms advance in their speed, ease-of-use, and cost-effectiveness, many researchers are transitioning from microarrays to RNA sequencing (or RNA-seq) for their gene expression analysis needs.
RNA-seq goes beyond differential gene expression to provide fundamental insights into how genomes are organized and regulated.
Some RNA-seq platforms also offer higher sensitivity, increased sample number flexibility, and the ability to analyze highly degraded or rare samples from as little as 10 ng of input RNA.
During this webinar, our expert speakers will discuss how NGS and RNA-seq can be broadly applied, including for the analysis of gene regulation through allelic expression and long non-coding RNAs, particularly in pharmacogenomics; for identification of novel microRNAs and transcript isoforms in stem cells; or for the discovery of new tumor biomarkers in archived formalin-fixed, paraffin-embedded samples.
During the webinar, viewers will:
• Hear about current approaches using RNA-seq for biomarker discovery
• Discover novel techniques using NGS for differential gene expression
• Learn what bioinformatics tools are being used in RNA-seq applications
• Have their questions answered live by our expert panel!
#306 follow-up
Sorry, forgot to add the link
http://app.aaas-science.org/e/.....9275a23527
#303 correction
Sorry, forgot to include the link
http://www.jointbscbbs.org/
OT
Check this comment:
#303, 304, 308 follow-up
Conference explores complex world of the dynamic cell
From mitosis to motors and microtubules – the latest in science’s understanding of the dynamic cell will be on show at a four-day conference in Cambridge, UK, this September.
The Dynamic Cell – a joint Biochemical Society and British Society of Cell Biology (BSCB) conference – will feature more than 40 speakers discussing the latest research into the molecular biology that underpins key cellular processes.
“Dynamic cell growth, division and movement are hallmarks of life and are essential for the formation of an organism, yet our understanding of the molecular basis of these processes is far from complete,” says BSCB Meetings Secretary Dr Stephen Royle.
“Our stellar line-up of speakers from the UK and around the world will showcase the most exciting and topical findings in dynamic cell biology, using different model organisms and both in vivo and in vitro approaches.”
Topics will cover cell migration and the cytoskeleton, cargo sorting in the endocytic and secretory pathways, molecular control of chromosome segregation and mitosis, membrane dynamics during cytokinesis, and in vitro analysis of molecular motors.
http://www.eurekalert.org/pub_.....062314.php
Protein Simulations
23—24 October 2014
Protein and enzyme function is determined by both structure and dynamic flexibility in solution.
Molecular simulations provide insight into conformational transitions that play a critical role in biological activity.
?Theoretical aspects of molecular dynamics simulations
?Preparation of a protein system for molecular dynamics simulations
?Practical aspects of running a simulation
?Output of simulations and analysis of trajectories
?Steered molecular dynamics
http://www.biochemistry.org/Co.....fault.aspx
Lighting Up pre-mRNA Recognition
Systematic analyses, by UV crosslinking, of the precise binding sites for 23 different proteins across the yeast pre-mRNA population have given insights into the in vivo assembly of, and interactions between, pre-mRNA processing, packaging, and transport complexes.
DOI: http://dx.doi.org/10.1016/j.molcel.2014.08.021
How chemistry supports cell biology: the chemical toolbox at your service
Chemical biology is a young and rapidly developing scientific field. In this field, chemistry is inspired by biology to create various tools to monitor and modulate biochemical and cell biological processes.
Chemical contributions such as small-molecule inhibitors and activity-based probes (ABPs) can provide new and unique insights into previously unexplored cellular processes.
Overview of recent breakthroughs in chemical biology that are likely to have a significant impact on cell biology.
Application of several chemical tools in cell biology research.
DOI: http://dx.doi.org/10.1016/j.tcb.2014.07.002
Absence of a simple code: how transcription factors read the genome
•TFs recognize their genomic target sites by using mechanisms at multiple levels.
•Models of DNA sequence and shape can capture the in vitro TF binding specificity.
•Cofactors, cooperativity, chromatin, and other factors affect in vivo TF binding.
•No simple code combines all the various determinants of TF binding specificity.
Transcription factors (TFs) influence cell fate by interpreting the regulatory DNA within a genome.
TFs recognize DNA in a specific manner; the mechanisms underlying this specificity have been identified for many TFs based on 3D structures of protein–DNA complexes.
More recently, structural views have been complemented with data from high-throughput in vitro and in vivo explorations of the DNA-binding preferences of many TFs.
Together, these approaches have greatly expanded our understanding of TF–DNA interactions.
However, the mechanisms by which TFs select in vivo binding sites and alter gene expression remain unclear.
Recent work has highlighted the many variables that influence TF–DNA binding, while demonstrating that a biophysical understanding of these many factors will be central to understanding TF function.
DOI: http://dx.doi.org/10.1016/j.tibs.2014.07.002
Long Noncoding RNAs Bind Active Chromatin Sites
Mechanistic roles for many lncRNAs are poorly understood, in part because their direct interactions with genomic loci and proteins are difficult to assess.
Using a method to purify endogenous RNAs and their associated factors, we mapped the genomic binding sites for two highly expressed human lncRNAs, NEAT1 and MALAT1.
We show that NEAT1 and MALAT1 localize to hundreds of genomic sites in human cells, primarily over active genes.
NEAT1 and MALAT1 exhibit colocalization to many of these loci, but display distinct gene body binding patterns at these sites, suggesting independent but complementary functions for these RNAs.
We also identified numerous proteins enriched by both lncRNAs, supporting complementary binding and function, in addition to unique associated proteins.
Transcriptional inhibition or stimulation alters localization of NEAT1 on active chromatin sites, implying that underlying DNA sequence does not target NEAT1 to chromatin, and that localization responds to cues involved in the transcription process.
DOI: http://dx.doi.org/10.1016/j.molcel.2014.07.012
unsuspected role of Notch signaling?
The regulatory inputs that drive lineage-restricted expression and how they relate to cell position are largely unknown?
Notch and Hippo Converge on Cdx2 to Specify the Trophectoderm Lineage?
The first lineage choice in mammalian embryogenesis is that between the trophectoderm, which gives rise to the trophoblast of the placenta, and the inner cell mass, from which is derived the embryo proper and the yolk sac.
The establishment of these lineages is preceded by the inside-versus-outside positioning of cells in the early embryo and stochastic expression of key transcription factors, which is then resolved into lineage-restricted expression.
The regulatory inputs that drive this restriction and how they relate to cell position are largely unknown.
Here, we show an unsuspected role of Notch signaling in regulating trophectoderm-specific expression of Cdx2 in cooperation with TEAD4.
Notch activity is restricted to outer cells and is able to influence positional allocation of blastomeres, mediating preferential localization to the trophectoderm.
Our results show that multiple signaling inputs at preimplantation stages specify the first embryonic lineages.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.019
A Self-Organizing miR-132/Ctbp2 Circuit Regulates Bimodal Notch Signals and Glial Progenitor Fate Choice during Spinal Cord Maturation
Radial glial progenitors play pivotal roles in the development and patterning of the spinal cord, and their fate is controlled by Notch signaling.
How Notch is shaped to regulate their crucial transition from expansion toward differentiation remains, however, unknown.
miR-132 in the developing zebrafish dampens Notch signaling via a cascade involving the transcriptional corepressor Ctbp2 and the Notch suppressor Sirt1.
At early embryonic stages, high Ctbp2 levels sustain Notch signaling and radial glial expansion and concomitantly induce miR-132 expression via a double-negative feedback loop involving Rest inhibition.
The changing balance in miR-132 and Ctbp2 interaction gradually drives the switch in Notch output and radial glial progenitor fate as part of the larger developmental program involved in the transition from embryonic to larval spinal cord.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.006
Mother Centrioles Do a Cartwheel to Produce Just One Daughter
In this issue of Developmental Cell, Fong et al. (2014) present evidence for a model of centriole duplication whereby the cartwheel—the starting building block in centriole biogenesis—assembles within the lumen of the mother centriole before templating the daughter centriole to ensure a single duplication event per cell cycle.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.013
High-Resolution Temporal Analysis Reveals a Functional Timeline for the Molecular Regulation of Cytokinesis
To take full advantage of fast-acting temperature-sensitive mutations, thermal control must be extremely rapid.
We developed the Therminator, a device capable of shifting sample temperature in ?17 s while simultaneously imaging cell division in vivo.
Applying this technology to six key regulators of cytokinesis, we found that each has a distinct temporal requirement in the Caenorhabditis elegans zygote.
Specifically, myosin-II is required throughout cytokinesis until contractile ring closure.
In contrast, formin-mediated actin nucleation is only required during assembly and early contractile ring constriction.
Centralspindlin is required to maintain division after ring closure, although its GAP activity is only required until just prior to closure.
Finally, the chromosomal passenger complex is required for cytokinesis only early in mitosis, but not during metaphase or cytokinesis.
Together, our results provide a precise functional timeline for molecular regulators of cytokinesis using the Therminator, a powerful tool for ultra-rapid protein inactivation.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.05.009
A Dynamic Microtubule Cytoskeleton Directs Medial Actomyosin Function during Tube Formation
The cytoskeleton is a major determinant of cell-shape changes that drive the formation of complex tissues during development.
Important roles for actomyosin during tissue morphogenesis have been identified, but the role of the microtubule cytoskeleton is less clear.
Here, we show that during tubulogenesis of the salivary glands in the fly embryo, the microtubule cytoskeleton undergoes major rearrangements, including a 90° change in alignment relative to the apicobasal axis, loss of centrosomal attachment, and apical stabilization.
Disruption of the microtubule cytoskeleton leads to failure of apical constriction in placodal cells fated to invaginate.
We show that this failure is due to loss of an apical medial actomyosin network whose pulsatile behavior in wild-type embryos drives the apical constriction of the cells.
The medial actomyosin network interacts with the minus ends of acentrosomal microtubule bundles through the cytolinker protein Shot, and disruption of Shot also impairs apical constriction.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.023
Do Endothelial Cells Dream of Eclectic Shape?
Endothelial cells (ECs) exhibit dramatic plasticity of form at the single- and collective-cell level during new vessel growth, adult vascular homeostasis, and pathology.
Understanding how, when, and why individual ECs coordinate decisions to change shape, in relation to the myriad of dynamic environmental signals, is key to understanding normal and pathological blood vessel behavior.
However, this is a complex spatial and temporal problem.
In this review we show that the multidisciplinary field of Adaptive Systems offers a refreshing perspective, common biological language, and straightforward toolkit that cell biologists can use to untangle the complexity of dynamic, morphogenetic systems.
DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.019
Integration of biological data by kernels on graph nodes allows prediction of new genes involved in mitotic chromosome condensation
The advent of genome-wide RNA interference (RNAi)–based screens puts us in the position to identify genes for all functions human cells carry out.
However, for many functions, assay complexity and cost make genome-scale knockdown experiments impossible.
Methods to predict genes required for cell functions are therefore needed to focus RNAi screens from the whole genome on the most likely candidates.
Although different bioinformatics tools for gene function prediction exist, they lack experimental validation and are therefore rarely used by experimentalists.
To address this, we developed an effective computational gene selection strategy that represents public data about genes as graphs and then analyzes these graphs using kernels on graph nodes to predict functional relationships.
To demonstrate its performance, we predicted human genes required for a poorly understood cellular function—mitotic chromosome condensation—and experimentally validated the top 100 candidates with a focused RNAi screen by automated microscopy.
Quantitative analysis of the images demonstrated that the candidates were indeed strongly enriched in condensation genes, including the discovery of several new factors.
By combining bioinformatics prediction with experimental validation, our study shows that kernels on graph nodes are powerful tools to integrate public biological data and predict genes involved in cellular functions of interest.
doi: 10.1091/mbc.E13-04-0221
Nup50 is required for cell differentiation and exhibits transcription-dependent dynamics
The nuclear pore complex (NPC) plays a critical role in gene expression by mediating import of transcription regulators into the nucleus and export of RNA transcripts to the cytoplasm.
Emerging evidence suggests that in addition to mediating transport, a subset of nucleoporins (Nups) engage in transcriptional activation and elongation at genomic loci that are not associated with NPCs.
The underlying mechanism and regulation of Nup mobility on and off nuclear pores remain unclear.
Here we show that Nup50 is a mobile Nup with a pronounced presence both at the NPC and in the nucleoplasm that can move between these different localizations.
Strikingly, the dynamic behavior of Nup50 in both locations is dependent on active transcription by RNA polymerase II and requires the N-terminal half of the protein, which contains importin ?– and Nup153-binding domains.
However, Nup50 dynamics are independent of importin ?, Nup153, and Nup98, even though the latter two proteins also exhibit transcription-dependent mobility.
Of interest, depletion of Nup50 from C2C12 myoblasts does not affect cell proliferation but inhibits differentiation into myotubes.
Taken together, our results suggest a transport-independent role for Nup50 in chromatin biology that occurs away from the NPC.
doi: 10.1091/mbc.E14-04-0865
http://www.molbiolcell.org/con.....6979c5409e
Cdk1 promotes cytokinesis in fission yeast through activation of the septation initiation network
In Schizosaccharomyces pombe, late mitotic events are coordinated with cytokinesis by the septation initiation network (SIN), an essential spindle pole body (SPB)–associated kinase cascade, which controls the formation, maintenance, and constriction of the cytokinetic ring.
It is not fully understood how SIN initiation is temporally regulated, but it depends on the activation of the GTPase Spg1, which is inhibited during interphase by the essential bipartite GTPase-activating protein Byr4-Cdc16.
Cells are particularly sensitive to the modulation of Byr4, which undergoes cell cycle–dependent phosphorylation presumed to regulate its function.
Polo-like kinase, which promotes SIN activation, is partially responsible for Byr4 phosphorylation.
Here we show that Byr4 is also controlled by cyclin-dependent kinase (Cdk1)–mediated phosphorylation.
A Cdk1 nonphosphorylatable Byr4 phosphomutant displays severe cell division defects, including the formation of elongated, multinucleate cells, failure to maintain the cytokinetic ring, and compromised SPB association of the SIN kinase Cdc7.
Our analyses show that Cdk1-mediated phosphoregulation of Byr4 facilitates complete removal of Byr4 from metaphase SPBs in concert with Plo1, revealing an unexpected role for Cdk1 in promoting cytokinesis through activation of the SIN pathway.
doi: 10.1091/mbc.E14-04-0936
http://www.molbiolcell.org/con.....6979c5409e
Mathematical model with spatially uniform regulation explains long-range bidirectional transport of early endosomes
In many cellular contexts, cargo is transported bidirectionally along microtubule bundles by dynein and kinesin-family motors.
Upstream factors influence how individual cargoes are locally regulated, as well as how long-range transport is regulated at the whole-cell scale.
Although the details of local, single-cargo bidirectional switching have been extensively studied, it remains to be elucidated how this results in cell-scale spatial organization.
Here we develop a mathematical model of early endosome transport in Ustilago maydis.
We demonstrate that spatiotemporally uniform regulation, with constant transition rates, results in cargo dynamics that is consistent with experimental data, including data from motor mutants.
We find that microtubule arrays can be symmetric in plus-end distribution but asymmetric in binding-site distribution in a manner that affects cargo dynamics and that cargo can travel past microtubule ends in microtubule bundles.
Our model makes several testable predictions, including secondary features of dynein and cargo distributions.
doi: 10.1091/mbc.E14-03-0826
http://www.molbiolcell.org/con.....4d441b9017
Kinetochore–microtubule attachment throughout mitosis potentiated by the elongated stalk of the kinetochore kinesin
Centromere protein E (CENP-E) is a highly elongated kinesin that transports pole-proximal chromosomes during congression in prometaphase.
During metaphase, it facilitates kinetochore–microtubule end-on attachment required to achieve and maintain chromosome alignment.
In vitro CENP-E can walk processively along microtubule tracks and follow both growing and shrinking microtubule plus ends.
Neither the CENP-E–dependent transport along microtubules nor its tip-tracking activity requires the unusually long coiled-coil stalk of CENP-E.
The biological role for the CENP-E stalk has now been identified through creation of “Bonsai” CENP-E with significantly shortened stalk but wild-type motor and tail domains.
We demonstrate that Bonsai CENP-E fails to bind microtubules in vitro unless a cargo is contemporaneously bound via its C-terminal tail.
In contrast, both full-length and truncated CENP-E that has no stalk and tail exhibit robust motility with and without cargo binding, highlighting the importance of CENP-E stalk for its activity.
Correspondingly, kinetochore attachment to microtubule ends is shown to be disrupted in cells whose CENP-E has a shortened stalk, thereby producing chromosome misalignment in metaphase and lagging chromosomes during anaphase.
Together these findings establish an unexpected role of CENP-E elongated stalk in ensuring stability of kinetochore–microtubule attachments during chromosome congression and segregation.
doi: 10.1091/mbc.E14-01-0698
http://www.molbiolcell.org/con.....4d441b9017
The surprising dynamics of scaffolding proteins
The function of scaffolding proteins is to bring together two or more proteins in a relatively stable configuration, hence their name.
Numerous scaffolding proteins are found in nature, many having multiple protein–protein interaction modules.
Over the past decade, examples of scaffolding complexes long thought to be stable have instead been found to be surprisingly dynamic.
These studies are scattered among different biological systems, and so the concept that scaffolding complexes might not always represent stable entities and that their dynamics can be regulated has not garnered general attention.
We became aware of this issue in our studies of a scaffolding protein in microvilli, which forced us to reevaluate its contribution to their structure.
The purpose of this Perspective is to draw attention to this phenomenon and discuss why complexes might show regulated dynamics.
We also wish to encourage more studies on the dynamics of “stable” complexes and to provide a word of caution about how functionally important dynamic associations may be missed in biochemical and proteomic studies.
doi: 10.1091/mbc.E14-04-0878
http://www.molbiolcell.org/con.....2e6bfedd87
The Centromere: Chromatin Foundation for the Kinetochore Machinery
DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.016
Since discovery of the centromere-specific histone H3 variant CENP-A, centromeres have come to be defined as chromatin structures that establish the assembly site for the complex kinetochore machinery.
In most organisms, centromere activity is defined epigenetically, rather than by specific DNA sequences.
In this review, we describe selected classic work and recent progress in studies of centromeric chromatin with a focus on vertebrates.
We consider possible roles for repetitive DNA sequences found at most centromeres, chromatin factors and modifications that assemble and activate CENP-A chromatin for kinetochore assembly, plus the use of artificial chromosomes and kinetochores to study centromere function.
Local CRH Signaling Promotes Synaptogenesis and Circuit Integration of Adult-Born Neurons
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.001
Neural activity either enhances or impairs de novo synaptogenesis and circuit integration of neurons, but how this activity is mechanistically relayed in the adult brain is largely unknown.
Neuropeptide-expressing interneurons are widespread throughout the brain and are key candidates for conveying neural activity downstream via neuromodulatory pathways that are distinct from classical neurotransmission.
With the goal of identifying signaling mechanisms that underlie neuronal circuit integration in the adult brain, we have virally traced local corticotropin-releasing hormone (CRH)-expressing inhibitory interneurons with extensive presynaptic inputs onto new neurons that are continuously integrated into the adult rodent olfactory bulb.
Local CRH signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation, and integration of new neurons in the adult brain.
A Gene Regulatory Network Controls the Binary Fate Decision of Rod and Bipolar Cells in the Vertebrate Retina
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.018
Gene regulatory networks (GRNs) regulate critical events during development.
In complex tissues, such as the mammalian central nervous system (CNS), networks likely provide the complex regulatory interactions needed to direct the specification of the many CNS cell types.
Here, we dissect a GRN that regulates a binary fate decision between two siblings in the murine retina, the rod photoreceptor and bipolar interneuron.
The GRN centers on Blimp1, one of the transcription factors (TFs) that regulates the rod versus bipolar cell fate decision.
We identified a cis-regulatory module (CRM), B108, that mimics Blimp1 expression.
Deletion of genomic B108 by CRISPR/Cas9 in vivo using electroporation abolished the function of Blimp1.
Otx2 and ROR? were found to regulate Blimp1 expression via B108, and Blimp1 and Otx2 were shown to form a negative feedback loop that regulates the level of Otx2, which regulates the production of the correct ratio of rods and bipolar cells.
In Directing Stem Cells, Study Shows Context Matters
Figuring out how blank slate stem cells decide which kind of cell they want to be when they grow up — a muscle cell, a bone cell, a neuron — has been no small task for science.
http://www.biosciencetechnolog.....cation=top
Single Cell Smashes, Rebuilds Its Own Genome
Life can be so intricate and novel that even a single cell can pack a few surprises, according to a study led by Princeton University researchers.
http://www.biosciencetechnolog.....8;type=cta
The ability to generate spontaneous motion and stable oscillations is a hallmark of living systems.
Cells crawl to heal wounds, and the heart contracts periodically to pump blood through the entire body.
Reproducing and understanding this behavior, both theoretically and experimentally, remains one of the great challenges of 21st-century science.
http://www.rdmag.com/news/2014.....cation=top
epigenetic regulation in development and aging
Briefings in Functional Genomics (2014)
13 (3): 223-234.
doi: 10.1093/bfgp/elt048
The precise developmental map of the Caenorhabditis elegans cell lineage, as well as a complete genome sequence and feasibility of genetic manipulation make this nematode species highly attractive to study the role of epigenetics during development.
Genetic dissection of phenotypical traits, such as formation of egg-laying organs or starvation-resistant dauer larvae, has illustrated how chromatin modifiers may regulate specific cell-fate decisions and behavioral programs.
Moreover, the transparent body of C. elegans facilitates non-invasive microscopy to study tissue-specific accumulation of heterochromatin at the nuclear periphery.
We also review here recent findings on how small RNA molecules contribute to epigenetic control of gene expression that can be propagated for several generations and eventually determine longevity.
http://bfg.oxfordjournals.org/.....7f990bb80b
epigenome reorganization during early embryogenesis
Briefings in Functional Genomics (2014)
13 (3): 246-253.
doi: 10.1093/bfgp/elu007
http://bfg.oxfordjournals.org/.....7f990bb80b
In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells.
During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization.
After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo.
Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role.
Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear.
This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications.
embryogenesis is governed by a series of signals that progressively define cell fate and shape the embryo. Nowadays, we know that such signals consist of regulatory mechanisms such as DNA methylation, histone modifications, long non-coding RNA and others.
Briefings in Functional Genomics (2014)
13 (3): 189-190.
doi: 10.1093/bfgp/elu008
http://bfg.oxfordjournals.org/.....7f990bb80b
Epigenetic regulation of the genome
Briefings in Functional Genomics (2014)
13 (3): 203-216.
doi: 10.1093/bfgp/elt047
http://bfg.oxfordjournals.org/.....7f990bb80b
Message control in developmental transitions
Briefings in Functional Genomics (2014)
13 (2): 106-120.
doi: 10.1093/bfgp/elt045
Now that the sequencing of genomes has become routine, understanding how a given genome is used in different ways to obtain cell type diversity in an organism is the next frontier.
How specific transcription programs are established during vertebrate embryogenesis, however, remains poorly understood.
Transcription is influenced by chromatin structure, which determines the accessibility of DNA-binding proteins to the genome.
Although large-scale genomics approaches have uncovered specific features of chromatin structure that are diagnostic for different cell types and developmental stages, our functional understanding of chromatin in transcriptional regulation during development is very limited.
In recent years, zebrafish embryogenesis has emerged as an excellent vertebrate model system to investigate the functional relationship between chromatin organization, gene regulation and development in a dynamic environment.
Here, we review how studies in zebrafish have started to improve our understanding of the role of chromatin structure in genome activation and pluripotency and in the potential inheritance of transcriptional states from parent to progeny.
http://bfg.oxfordjournals.org/.....7f990bb80b
Congenital heart diseases (CHD) represent the most common birth defect in human.
The majority of cases are caused by a combination of complex genetic alterations and environmental influences.
In the past, many disease-causing mutations have been identified; however, there is still a large proportion of cardiac malformations with unknown precise origin.
High-throughput sequencing technologies established during the last years offer novel opportunities to further study the genetic background underlying the disease.
In this review, we provide a roadmap for designing and analyzing high-throughput sequencing studies focused on CHD, but also with general applicability to other complex diseases.
The three main next-generation sequencing (NGS) platforms including their particular advantages and disadvantages are presented.
To identify potentially disease-related genomic variations and genes, different filtering steps and gene prioritization strategies are discussed.
In addition, available control datasets based on NGS are summarized.
Finally, we provide an overview of current studies already using NGS technologies and showing that these techniques will help to further unravel the complex genetics underlying CHD.
Briefings in Functional Genomics (2014)
13 (1): 51-65.
doi: 10.1093/bfgp/elt040
http://bfg.oxfordjournals.org/.....0a4e37cccc
Genomics of cardiac electrical function
Proper generation and conduction of the cardiac electrical impulse is essential for the continuous coordinated contraction of the heart.
Dysregulation of cardiac electrical function may lead to cardiac arrhythmias, which constitute a huge medical and social burden.
Identifying the genetic factors underlying cardiac electrical activity serves the double purpose of allowing the early identification of individuals at risk for arrhythmia and discovering new potential therapeutic targets for prevention.
The aim of this review is to provide an overview of the genes and genetic loci linked thus far to cardiac electrical function and arrhythmia.
These genes and loci have been primarily uncovered through studies on the familial rhythm disorders and through genome-wide association studies on electrocardiographic parameters in large sets of the general population.
An overview of all genes and loci with their respective effect is given.
Briefings in Functional Genomics (2014)
13 (1): 39-50.
doi: 10.1093/bfgp/elt029
http://bfg.oxfordjournals.org/.....0a4e37cccc
on the frenetic hunt for new cytosine modifications
Briefings in Functional Genomics (2013)
12 (3): 191-204.
doi: 10.1093/bfgp/elt010
http://bfg.oxfordjournals.org/.....0a4e37cccc
Epigenetic genome marking and chromatin regulation are central to establishing tissue-specific gene expression programs, and hence to several biological processes.
Until recently, the only known epigenetic mark on DNA in mammals was 5-methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression.
All of a sudden, a host of new actors—novel cytosine modifications and the ten eleven translocation (TET) enzymes—has appeared on the scene, sparking great interest.
The challenge is now to uncover the roles they play and how they relate to DNA demethylation.
Knowledge is accumulating at a frantic pace, linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis.
Here, we review the recent progress in this exciting field, highlighting the TET enzymes as epigenetic DNA modifiers, their physiological roles, and their functions in health and disease.
We also discuss the need to find relevant TET interactants and the newly discovered TET–O-linked N-acetylglucosamine transferase (OGT) pathway.
Fertilization video
https://www.youtube.com/embed/_5OvgQW6FG4?rel=0
Chromosome and Kinetochore in Mitosis video
https://www.youtube.com/embed/0JpOJ4F4984?rel=0
Metabolic programming of mesenchymal stromal cells by oxygen tension directs chondrogenic cell fate
doi: 10.1073/pnas.1410977111
Multipotent cells, such as mesenchymal stromal cells (MSCs), have the capacity to differentiate into cartilage-forming cells.
Chondrocytes derived from MSCs obtain an epiphyseal cartilage-like phenotype, which turns into bone upon implantation via endochondral ossification.
Here, we report that the chondrogenic fate of MSCs can be metabolically programmed by low oxygen tension to acquire an articular chondrocyte-like phenotype via mechanisms that resemble natural development.
Our study identifies metabolic programming of stem cells by oxygen tension as a powerful tool to control cell fate, which may have broad applications for the way in which stem cells are now prepared for clinical use.
————
Actively steering the chondrogenic differentiation of mesenchymal stromal cells (MSCs) into either permanent cartilage or hypertrophic cartilage destined to be replaced by bone has not yet been possible.
During limb development, the developing long bone is exposed to a concentration gradient of oxygen, with lower oxygen tension in the region destined to become articular cartilage and higher oxygen tension in transient hypertrophic cartilage.
Here, we prove that metabolic programming of MSCs by oxygen tension directs chondrogenesis into either permanent or transient hyaline cartilage.
Human MSCs chondrogenically differentiated in vitro under hypoxia (2.5% O2) produced more hyaline cartilage, which expressed typical articular cartilage biomarkers, including established inhibitors of hypertrophic differentiation.
In contrast, normoxia (21% O2) prevented the expression of these inhibitors and was associated with increased hypertrophic differentiation.
Interestingly, gene network analysis revealed that oxygen tension resulted in metabolic programming of the MSCs directing chondrogenesis into articular- or epiphyseal cartilage-like tissue.
This differentiation program resembled the embryological development of these distinct types of hyaline cartilage.
Remarkably, the distinct cartilage phenotypes were preserved upon implantation in mice.
Hypoxia-preconditioned implants remained cartilaginous, whereas normoxia-preconditioned implants readily underwent calcification, vascular invasion, and subsequent endochondral ossification.
In conclusion, metabolic programming of MSCs by oxygen tension provides a simple yet effective mechanism by which to direct the chondrogenic differentiation program into either permanent articular-like cartilage or hypertrophic cartilage that is destined to become endochondral bone.
http://www.pnas.org/content/ea.....122cab965b
Three-dimensional cell body shape dictates the onset of traction force generation and growth of focal adhesions
doi: 10.1073/pnas.1411785111
PNAS September 9, 2014 vol. 111 no. 36 13075-13080
Living cells interact with their environment through surface receptors.
In particular, adhesion molecules form complexes that anchor cells to each other and to the extracellular matrix.
These complexes ensure mechanical integrity of tissues and control cell function through specific biochemical signaling.
This dual role is due to the ability of adhesion complexes to grow and change their composition and activity in response to mechanical forces.
Here, we show how cell spreading, by modifying cell shape, controls the distribution of internal tension over adhesion complexes, inducing their growth above a well-defined spread area.
Because such a threshold area was reported for many cell functions, our findings shed a new light on the possible mechanisms behind the geometric control of cell fate.
———–
Cell shape affects proliferation and differentiation, which are processes known to depend on integrin-based focal adhesion (FA) signaling.
Because shape results from force balance and FAs are mechanosensitive complexes transmitting tension from the cell structure to its mechanical environment, we investigated the interplay between 3D cell shape, traction forces generated through the cell body, and FA growth during early spreading.
Combining measurements of cell-scale normal traction forces with FA monitoring, we show that the cell body contact angle controls the onset of force generation and, subsequently, the initiation of FA growth at the leading edge of the lamella.
This suggests that, when the cell body switches from convex to concave, tension in the apical cortex is transmitted to the lamella where force-sensitive FAs start to grow.
Along this line, increasing the stiffness resisting cell body contraction led to a decrease of the lag time between force generation and FA growth, indicating mechanical continuity of the cell structure and force transmission from the cell body to the leading edge.
Remarkably, the overall normal force per unit area of FA increased with stiffness, and its values were similar to those reported for local tangential forces acting on individual FAs.
These results reveal how the 3D cell shape feeds back on its internal organization and how it may control cell fate through FA-based signaling.
http://www.pnas.org/content/11.....122cab965b
Custos controls ?-catenin to regulate head development during vertebrate embryogenesis
doi: 10.1073/pnas.1414437111
PNAS September 9, 2014 vol. 111 no. 36 13099-13104
Canonical Wnt pathway is essential for primary axis formation and establishment of basic body pattern during embryogenesis.
Defects in Wnt signaling have also been implicated in tumorigenesis and birth defect disorders.
Here we characterize a novel component of canonical Wnt signaling termed Custos and show that this protein binds to and modulates ?-catenin nuclear translocation in the canonical Wnt signal transduction cascade.
Our functional characterization of Custos further shows that this protein has a conserved role in development, being essential for organizer formation and subsequent anterior development in the Xenopus and zebrafish embryo.
These studies unravel a new layer of regulation of canonical Wnt signaling that might provide insights into mechanisms by which deregulated Wnt signaling results in pathological disorders.
—–
Precise control of the canonical Wnt pathway is crucial in embryogenesis and all stages of life, and dysregulation of this pathway is implicated in many human diseases including cancers and birth defect disorders.
A key aspect of canonical Wnt signaling is the cytoplasmic to nuclear translocation of ?-catenin, a process that remains incompletely understood.
Here we report the identification of a previously undescribed component of the canonical Wnt signaling pathway termed Custos, originally isolated as a Dishevelled–interacting protein.
Custos contains casein kinase phosphorylation sites and nuclear localization sequences. In Xenopus, custos mRNA is expressed maternally and then widely throughout embryogenesis.
Depletion or overexpression of Custos produced defective anterior head structures by inhibiting the formation of the Spemann-Mangold organizer.
In addition, Custos expression blocked secondary axis induction by positive signaling components of the canonical Wnt pathway and inhibited ?-catenin/TCF-dependent transcription.
Custos binds to ?-catenin in a Wnt responsive manner without affecting its stability, but rather modulates the cytoplasmic to nuclear translocation of ?-catenin.
This effect on nuclear import appears to be the mechanism by which Custos inhibits canonical Wnt signaling.
The function of Custos is conserved as loss-of-function and gain-of-function studies in zebrafish also demonstrate a role for Custos in anterior head development.
Our studies suggest a role for Custos in fine-tuning canonical Wnt signal transduction during embryogenesis, adding an additional layer of regulatory control in the Wnt-?-catenin signal transduction cascade.
http://www.pnas.org/content/11......html?etoc
Transmission of a signal that synchronizes cell movements
doi: 10.1073/pnas.1411925111
PNAS September 9, 2014 vol. 111 no. 36 13105-13110
Multicellular organisms, by necessity[?], form highly organized structures.
The mechanisms required to construct these often dynamic structures are a challenge to understand.
Myxococcus xanthus, a soil bacterium, builds two large structures: growing swarms and fruiting bodies.
Because the cells are genetically identical, they rely on regulating protein activity and the levels of gene expression.
Moreover, the long, flexible, rod-shaped cells modify each others’ behavior when they collide.
By examining development of a Myxococcus swarm, testable rules can be proposed that rely only on cell behavior and cell–cell contact signaling.
The mechanisms used by this prokaryote to form complex, dynamic multicellular structures might have been adapted for Hedgehog and Wnt morphogenetic signaling in animals.[how?]
—–
We offer evidence for a signal that synchronizes the behavior of hundreds of Myxococcus xanthus cells in a growing swarm.
Swarms are driven to expand by the periodic reversing of direction by members.
By using time-lapse photomicroscopy, two organized multicellular elements of the swarm were analyzed: single-layered, rectangular rafts and round, multilayered mounds.
Rafts of hundreds of cells with their long axes aligned in parallel enlarge as individual cells from the neighborhood join them from either side.
Rafts can also add a second layer piece by piece.
By repeating layer additions to a raft and rounding each layer, a regular multilayered mound can be formed.
About an hour after a five-layered mound had formed, all of the cells from its top layer descended to the periphery of the fourth layer, both rapidly and synchronously.
Following the first synchronized descent and spaced at constant time intervals, a new fifth layer was (re)constructed from fourth-layer cells, in very close proximity to its old position and with a number of cells similar to that before the “explosive” descent.
This unexpected series of changes in mound structure can be explained by the spread of a signal that synchronizes the reversals of large groups of individual cells.
http://www.pnas.org/content/11......html?etoc
Do they mention how new functionality arises?
Interspecific Variation in Rx1 Expression Controls Opsin Expression and Causes Visual System Diversity in African Cichlid Fisches
Mol Biol Evol (2014)
31 (9): 2297-2308.
doi: 10.1093/molbev/msu172
The mechanisms underlying natural phenotypic diversity are key to understanding evolution and speciation. Cichlid fishes are among the most speciose vertebrates and an ideal model for identifying genes controlling species differences. Cichlids have diverse visual sensitivities that result from species expressing subsets of seven cichlid cone opsin genes. We previously identified a quantitative trait locus (QTL) that tunes visual sensitivity by varying SWS2A (short wavelength sensitive 2A) opsin expression in a genetic cross between two Lake Malawi cichlid species. Here, we identify Rx1 (retinal and anterior neural fold homeobox) as the causative gene for the QTL using fine mapping and RNAseq in retinal transcriptomes. Rx1 is differentially expressed between the parental species and correlated with SWS2A expression in the F2 progeny. Expression of Rx1 and SWS2A is also correlated in a panel of 16 Lake Malawi cichlid species. Association mapping in this panel identified a 413-bp deletion located 2.5-kb upstream of the Rx1 translation start site that is correlated with decreased Rx1 expression. This deletion explains 62% of the variance in SWS2A expression across 53 cichlid species in 29 genera. The deletion occurs in both the sand and rock-dwelling cichlid clades, suggesting that it is an ancestral polymorphism. Our finding supports the hypothesis that mixing and matching of ancestral polymorphisms can explain the diversity of present day cichlid phenotypes.
Restoring totipotency through epigenetic reprogramming
Briefings in Functional Genomics (2013)
12 (2): 118-128.
doi: 10.1093/bfgp/els042
Epigenetic modifications are implicated in the maintenance and regulation of transcriptional memory by marking genes that were previously transcribed to facilitate transmission of these expression patterns through cell division.
During germline specification and maintenance, extensive epigenetic modifications are acquired.
Yet somehow at fertilization, the fusion of the highly differentiated sperm and egg results in formation of the totipotent zygote.
This massive change in cell fate implies that the selective erasure and maintenance of epigenetic modifications at fertilization may be critical for the re-establishment of totipotency.
In this review, we discuss recent studies that provide insight into the extensive epigenetic reprogramming that occurs around fertilization and the mechanisms that may be involved in the re-establishment of totipotency in the embryo.
http://bfg.oxfordjournals.org/.....0998e03ceb
The past decades have revealed an unexpected yet prominent role of so-called ‘junk DNA’ in the regulation of gene expression, thereby challenging our view of the mechanisms underlying phenotypic evolution.
In particular, several mechanisms through which transposable elements (TEs) participate in functional genome diversity have been depicted, bringing to light the ‘TEs bright side’.
However, the relative contribution of those mechanisms and, more generally, the importance of TE-based polymorphisms on past and present phenotypic variation in crops species remain poorly understood.
Briefings in Functional Genomics (2014)
13 (4): 276-295.
doi: 10.1093/bfgp/elu002
http://bfg.oxfordjournals.org/.....cfe19c039c
epigenome reorganization during oocyte differentiation and early embryogenesis
Briefings in Functional Genomics (2014)
13 (3): 246-253.
doi: 10.1093/bfgp/elu007
In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells.
During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization.
After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo.
Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role.
Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear.
This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications.
http://bfg.oxfordjournals.org/.....73957d97ea
How…, how…, how…???
Epigenetic mechanisms and developmental choice hierarchies in development
Briefings in Functional Genomics (2013)
12 (6): 512-524.
doi: 10.1093/bfgp/elt027
Three interlocking problems in gene regulation are:
how to explain genome-wide targeting of transcription factors in different cell types,
how prior transcription factor action can establish an ‘epigenetic state’ that changes the options for future transcription factor action, and
how directly a sequence of developmental decisions can be memorialized in a hierarchy of repression structures applied to key genes of the ‘paths not taken’.
This review uses the finely staged process of T-cell lineage commitment as a test case in which to examine how changes in developmental status are reflected in changes in transcription factor expression, transcription factor binding distribution across genomic sites, and chromatin modification.
These are evaluated in a framework of reciprocal effects of previous chromatin structure features on transcription factor access and of transcription factor binding on other factors and on future chromatin structure.
http://bfg.oxfordjournals.org/.....73957d97ea
From ‘JUNK’ to Just Unexplored Noncoding Knowledge: the case of transcribed Alus
Briefings in Functional Genomics
10 (5): 294-311.
doi: 10.1093/bfgp/elr029
Non-coding RNAs (ncRNAs) are increasingly being implicated in diverse functional roles.
Majority of these ncRNAs have their origin in the repetitive elements of genome.
Significantly, increase in genomic complexity has been correlated with increase in repetitive content of the genome.
Of the many possible functional roles of Alu repeats, they have been shown to modulate human transcriptome by virtue of harboring diverse array of functional RNA pol II TFBS, cryptic splice-site-mediated Alu exonization and as probable miRNA targets.
Retro-transposition of Alu harboring TFBS has shaped up gene-specific regulatory networks.
Alu exonized transcripts are raw material for dsRNA-mediated A–I editing leading to nuclear retention of transcripts and change in miRNA target.
miRNA targets within Alu may titrate the effective miRNA or transcript concentration, thus acting as ‘miRNA sponge’. Differential levels of Alu RNA during different conditions of stress also await clear functional understanding.
Recent reports of co-localization of pol II and pol III binding sites near the gene and elsewhere in the genome, increase the possibility of dynamic co-ordination between both pol II and pol III determining the ultimate transcriptional outcome.
Dynamic and functional Alu repeats seem to be centrally placed to modulate the transcriptional landscape of human genome.
http://bfg.oxfordjournals.org/.....5/294.full
Role of lncRNAs in health and disease—size and shape matter
Most of the mammalian genome including a large fraction of the non-protein coding transcripts has been shown to be transcribed.
Studies related to these non-coding RNA molecules have predominantly focused on smaller molecules like microRNAs.
In contrast, long non-coding RNAs (lncRNAs) have long been considered to be transcriptional noise.
Accumulating evidence suggests that lncRNAs are involved in key cellular and developmental processes.
Several critical questions regarding functions and properties of lncRNAs and their circular forms remain to be answered.
Increasing evidence from high-throughput sequencing screens also suggests the involvement of lncRNAs in diseases such as cancer, although the underlying mechanisms still need to be elucidated.
Here, we discuss the current state of research in the field of lncRNAs, questions that need to be addressed in light of recent genome-wide studies documenting the landscape of lncRNAs, their functional roles and involvement in diseases.
We posit that with the availability of high-throughput data sets it is not only possible to improve methods for predicting lncRNAs but will also facilitate our ability to elucidate their functions and phenotypes by using integrative approaches.
Briefings in Functional Genomics (2014)
doi: 10.1093/bfgp/elu034
http://bfg.oxfordjournals.org/.....72d5abe451
Synthetic biology at the interface of functional genomics
Briefings in Functional Genomics (2014)
doi: 10.1093/bfgp/elu031
Functional genomics is considered a powerful tool that helps understand the relation between an organism’s genotype and possible phenotypes.
Volumes of data generated on several ‘omics’ platforms have revealed the network complexities underlying biological processes.
Systems and synthetic biology have garnered much attention because of the ability to infer and comprehend the uncertainties associated with such complexities.
Also, part-wise characterization of the network components (e.g. DNA, RNA, protein) has rendered an engineering perspective in life sciences to build modular and functional devices.
This approach can be used to combat one of the many concerns of the world, i.e. in the area of biomedical translational research by designing and constructing novel therapeutic devices to intervene network perturbation in a diseased state to transform to a healthy state.
http://bfg.oxfordjournals.org/.....72d5abe451
Regulation of cell fate determination
Building a multicellular organism from a single cell requires the coordinated formation of different cell types in a spatiotemporal arrangement.
How different cell types arise in appropriate places and at appropriate times is one of the most intensively investigated questions in modern biology.
doi: 10.3389/fpls.2014.00368
http://journal.frontiersin.org.....00368/full
Involvement of certain proteins in the regulation of cell fate determination
DOI: 10.1111/jipb.12221
Cell fate determination is a basic developmental process during the growth of multicellular organisms.
Trichomes and root hairs of Arabidopsis are both readily accessible structures originating from the epidermal cells of the aerial tissues and roots respectively, and they serve as excellent models for understanding the molecular mechanisms controlling cell fate determination and cell morphogenesis.
The regulation of trichome and root hair formation is a complex program that consists of the integration of hormonal signals with a large number of transcriptional factors, including MYB and bHLH transcriptional factors.
Studies during recent years have uncovered an important role of C2H2 type zinc finger proteins in the regulation of epidermal cell fate determination.
Here in this minireview we briefly summarize the involvement of C2H2 zinc finger proteins in the control of trichome and root hair formation in Arabidopsis
http://onlinelibrary.wiley.com.....1/abstract
Influence of the microenvironment on cell fate determination and migration
DOI: 10.1152/physiolgenomics.00170.2013
Several critical cell functions are influenced not only by internal cellular machinery but also by external mechanical and biochemical cues from the surrounding microenvironment.
Slight changes to the microenvironment can result in dramatic changes to the cell’s phenotype; for example, a change in the nutrients or pH of a tumor microenvironment can result in increased tumor metastasis.
While cellular fate and the regulators of cell fate have been studied in detail for several decades now, our understanding of the extracellular regulators remains qualitative and far from comprehensive.
In this review, we discuss the microenvironment influence on cell fate in terms of adhesion, migration, and differentiation and focus on both developments in experimental and computation tools to analyze cellular fate
http://physiolgenomics.physiol.....t/46/9/309
system regulates cell fate determination of stem cells
DOI: 10.1111/gtc.12126
Nrf2 is a major transcriptional activator of cytoprotective genes against oxidative/electrophilic stress, and Keap1 negatively regulates Nrf2.
Emerging works have also suggested a role for Nrf2 as a regulator of differentiation in various cells, but the contribution of Nrf2 to the differentiation of hematopoietic stem cells (HSCs) remains elusive.
Clarifying this point is important to understand Nrf2 functions in the development and/or resolution of inflammation.
Here, we established two transgenic reporter mouse lines that allowed us to examine Nrf2 expression precisely in HSCs.
Nrf2 was abundantly transcribed in HSCs, but its activity was maintained at low levels due to the Keap1-mediated degradation of Nrf2 protein.
When we characterized Keap1-deficient mice, their bone marrow cells showed enhanced granulocyte-monocyte differentiation at the expense of erythroid and lymphoid differentiation.
@Importantly, Keap1-null HSCs showed lower expression of erythroid and lymphoid genes than did control HSCs, suggesting granulocyte-monocyte lineage priming in Keap1-null HSCs.
This abnormal lineage commitment was restored by a concomitant deletion of Nrf2, demonstrating the Nrf2-dependency of the skewing.
Analysis of Nrf2-deficient mice revealed that the physiological level of Nrf2 is sufficient to contribute to the lineage commitment.
This study unequivocally shows that the Keap1-Nrf2 system regulates the cell fate determination of HSCs.
http://onlinelibrary.wiley.com.....6/abstract
Mature T cells can switch function to better tackle infection
Helper cells of the immune system can switch to become killer cells in the gut
The fate of mature T lymphocytes might be a lot more flexible than previously thought.
http://www.riken.jp/en/pr/press/2013/20130121_1/
Insights into the geometry of genetic coding
DOI: 10.1038/nature13440
http://www.riken.jp/en/pr/press/2014/20140612_1/
lymphatic cell fate specification pathways
doi: 10.1242/dev.105031
http://www.ncbi.nlm.nih.gov/pubmed/24523456
Specification of epidermal cell fate in plant shoots
Land plants have a single layer of epidermal cells, which are characterized by mostly anticlinal cell division patterns, formation of a waterproof coat called cuticle, and unique cell types such as stomatal guard cells and trichomes.
The shoot epidermis plays important roles not only to protect plants from dehydration and pathogens but also to ensure their proper organogenesis and growth control.
Extensive molecular genetic studies in Arabidopsis and maize have identified a number of genes that are required for epidermal cell differentiation.
However, the mechanism that specifies shoot epidermal cell fate during plant organogenesis remains largely unknown.
Particularly, little is known regarding positional information that should restrict epidermal cell fate to the outermost cell layer of the developing organs.
Recent studies suggested that certain members of the HD-ZIP class IV homeobox genes are possible master regulators of shoot epidermal cell fate.
Here, we summarize the roles of the regulatory genes that are involved in epidermal cell fate specification and discuss the possible mechanisms that limit the expression and/or activity of the master transcriptional regulators to the outermost cell layer in plant shoots.
doi: 10.3389/fpls.2014.00049
http://journal.frontiersin.org.....00049/full
Autonomous Cell Fate Specification
DOI: 10.1002/9780470015902.a0001148.pub3
Autonomous cell fate specification is a form of embryonic specification in which a developing cell is able to differentiate (become a cell carrying out a specialized function) without receiving external signals.
This property is enabled by cytoplasmic determinants (cytoplasmic regulatory factors necessary for specification) that are deposited in different regions of the ovum during oogenesis.
These cytoplasmic determinants are partitioned into individual cells during embryonic cleavage, and thus endow these cells with the ability to form specific cell types.
If an autonomously specified cell is removed from the embryo during early development and cultured in isolation, that cell will produce the descendants that it would have normally produced in the undisturbed embryo.
Frequently, the embryo from which the cell was removed lacks the structures normally made by the missing cell.
Autonomous cell fate specification is often used during patterning of invertebrate embryos such as ctenophores, annelids, molluscs, echinoderms and tunicates.
http://www.els.net/WileyCDA/El.....01148.html
Pioneer Transcription Factors in Cell Fate Specification
DOI: http://dx.doi.org/10.1210/me.2014-1084
The specification of cell fate is critical for proper cell differentiation and organogenesis.
http://press.endocrine.org/doi......2014-1084
Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification.
doi: 10.1242/dev.101709.
The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs).
Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers.
Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities.
Furthermore, clustering the top-scoring classifier sequence features identified novel cardiac and cell type-specific regulatory motifs.
For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions.
In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities.
Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks.
http://www.ncbi.nlm.nih.gov/pubmed/24496624
Enhancers: emerging roles in cell fate specification.
doi: 10.1038/embor.2012.52.
Enhancers are regulatory DNA elements that dictate the spatial and temporal patterns of gene expression during development.
Recent evidence suggests that the distinct chromatin features of enhancer regions provide the permissive landscape required for the differential access of diverse signalling molecules that drive cell-specific gene expression programmes.
The epigenetic patterning of enhancers occurs before cell fate decisions, suggesting that the epigenetic information required for subsequent differentiation processes is embedded within the enhancer element.
Lineage studies indicate that the patterning of enhancers might be regulated by the intricate interplay between DNA methylation status, the binding of specific transcription factors to enhancers and existing histone modifications.
In this review, we present insights into the mechanisms of enhancer function, which might ultimately facilitate cell reprogramming strategies for use in regenerative medicine.
http://www.ncbi.nlm.nih.gov/pubmed/22491032
Chromatin stretch enhancer states drive cell-specific gene regulation
doi: 10.1073/pnas.1317023110
Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases.
Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets.
Integrated analysis of islet data with those from nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers.
Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb).
Each cell type also contains a substantial number of more extended (? 3 kb) enhancers.
Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons.
Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers.
Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice.
These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases.
http://www.ncbi.nlm.nih.gov/pubmed/24127591
Diverse patterns of genomic targeting by transcriptional regulators
doi: 10.1101/gr.168807.113.
http://www.ncbi.nlm.nih.gov/pubmed/24985916
Polarized Wnt Signaling Regulates Ectodermal Cell Fate
doi:10.1016/j.devcel.2014.03.015
How cells convert polarity cues into cell fate specification is incompletely understood
https://www.gene-tools.com/content/polarized-wnt-signaling-regulates-ectodermal-cell-fate-xenopus
Stem Cell Activation and Cell Fate Specification
Cell communication between tissue stem cells and their cellular microenvironment within so-called stem cell niches is critical for stem cell self-renewal, differentiation and thus overall tissue homeostasis.
But how these specialized niche cells acquire their inductive properties generally remains unknown.
http://research.mssm.edu/rendl/research.html
Cell fate specification and determination
During development, cells are undergoing differentiation. Often, cells are discussed in terms of their terminal differentiation state.
During development, fates of cells may be specified at certain times.
When referring to developmental fate or cell fate, one is talking about everything that happens to that cell and its progeny after that point in development.
The process of a cell to be committed to a certain state can be divided into two stages: specification and determination.
Specification is not a permanent stage and cells can be reversed based upon different cues.
In contrast, determination refers to when cells are irreversibly committed to a particular fate.
The state of commitment of a cell is also known as its developmental potential.
When the developmental potential is less than or equal to the developmental fate, the cell is exhibiting mosaic behavior.
When the developmental potential is greater than the developmental fate, the cell is exhibiting regulative behavior.
Embryos can use a combination of methods and exhibit a combination of behaviors throughout its development.
Types of specification
There are three major ways that developmental fates become specified: autonomous specification, conditional specification and syncytial specification.
Autonomous specification
This type of specification results from cell-intrinsic properties; it gives rise to mosaic development.
The cell-intrinsic properties arise from a cleavage of a cell with asymmetric cytoplasmic determinants or morphogenetic determinants.
Thus, the fate of the cell depends on factors segregated into the cytoplasm during cleavage.
Early examples of autonomous specification came from the work of Whittaker in tunicate embryos.
Conditional specification
In contrast to the autonomous specification, this type of specification is a cell-extrinsic process that relies on cues and interactions between cells or from concentration-gradients of morphogens.
These interactions can be either stimulatory or inhibitory. This type of specification was discovered from the result of transplantation experiments and isolation experiments.
Syncytial specification
This type of a specification is a hybrid of the autonomous and conditional that occurs in insects.
This method involves the action of morphogen gradients within the syncytium.
As there are no cell boundaries in the syncytium, these morphogens can influence nuclei in a concentration-dependent manner.
http://www.bionity.com/en/ency.....ation.html
(In)sights Into Pluripotency, Cell Fate Specification, and Tissue Formation
http://www.mskcc.org/events/sk.....-formation
An embryonic cell’s fate is sealed by the speed of a signal
When embryonic cells get the signal to specialize the call can come quickly. Or it can arrive slowly.
Now, new research from Rockefeller University suggests the speed at which a cell in an embryo receives that signal has an unexpected influence on that cell’s fate.
Until now, only concentration of the chemical signals was thought to matter in determining if the cell would become, for example, muscle, skin, brain or bone.
“It turns out that if ramped up slowly enough an otherwise potent signal elicits no response from the receiving cells.
Meanwhile, a pulsing, on-off signal appears to have a stronger effect than a constant one,”
http://www.ecnmag.com/news/201.....eed-signal
Cell Fate Specification by Localized Cytoplasmic Determinants and Cell Interactions
DOI: 10.1016/S0074-7696(08)61612-5
how the fate of each blastomere becomes specified during development
interesting features concerning cellular mechanisms responsible for the fate specification
During embryogenesis, the developmental fate of a blastomere is specified by one of three different mechanisms:
-localized maternal cytoplasmic determinants,
-inductive interactions, or
-lateral inhibition in an equivalence cell group
http://www.sciencedirect.com/s.....9608616125
Dionisio:
Thank you so much for your continuing effort in giving us such precious references from the scientific literature. You really find the important things!
I hope that many others, like me, will read those papers and reflect on them.
gpuccio
Thank you for encouraging me to stick to biology when someone visiting this blog earlier this year suggested that I better get out of this blog and go back to my previous engineering work. Do you remember that incident?
The learning process hasn’t ben easy for me, but now I understand a little more than I did 6 months ago.
BTW, have you used Mind Meister to organize research documents?
Neural Crest: Origin, Migration and Differentiation
DOI: 10.1002/9780470015902.a0000786.pub2
The neural crest is a population of cells that emigrates from the dorsal neural tube during early embryogenesis and migrates extensively to give rise to a myriad of cell types.
Patterns of migration are controlled largely by extracellular cues in the environment. Neural crest cells are initially multipotent.
Cell fate specification – the selection of an individual cell fate from all the possibilities available to a multipotent progenitor – is likely to involve a series of steps, in which cells become progressively restricted to individual fates, a process that is likely to begin while still in the dorsal neural tube, but which then is usually completed during, or even after migration.
Extracellular cues in the migratory and postmigratory environment act together with intrinsic transcription factors to ensure that specific fates are chosen.
Together, these result in expression of one or more transcription factors that activate or cement a gene regulatory network that establishes and maintains expression of the differentiated phenotype.
http://www.els.net/WileyCDA/El.....00786.html
A cell’s lineage describes the developmental history of a cell from its birth until its final division and differentiation into a particular cell type, which is known as its cell fate.
Cell fate is determined by the actions of numerous cell intrinsic and extrinsic factors.
Cell fate
The patterns of fate
doi:10.1038/nrn3643
The mechanisms determining neural progenitor cell (NPC) fate choices remain incompletely understood.
NPC differentiation is associated with the sustained, dominant expression of particular transcription factors, whereas the proliferation of NPCs is associated with oscillating patterns of expression of several factors.
http://www.nature.com/nrn/jour.....n3643.html
Sophisticated genetic methods for cell type identification have increased our understanding of cell fate acquisition during development.
doi:10.1038/nrn3751
http://www.nature.com/nrn/jour.....n3751.html
Development
Branched for function
doi:10.1038/nrn3579
Unique combinations of transcription factors are known to distinguish neuronal fates, but the downstream mechanisms that specify neuronal morphology are poorly understood.
http://www.nature.com/nrn/jour.....n3579.html
Neural development
Tracing interneuron roots
doi:10.1038/nrn3628
Interneurons make up 25% of human cortical neurons, but their developmental origins remain mysterious.
http://www.nature.com/nrn/jour.....n3628.html
Fez family transcription factors: Controlling neurogenesis and cell fate in the developing nervous system
DOI: 10.1002/bies.201400039
Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos.
These proteins share an N-terminal domain with homology to the canonical engrailed repressor motif and a C-terminal DNA binding domain containing six C2H2 zinc-finger repeats.
Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice.
Herein we discuss recent progress in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development.
Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners.
Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types.
http://onlinelibrary.wiley.com.....9/abstract
Plant biology examples of cell fate specification and determination mechanisms.
Mechanisms to control bundle sheath cell fate and function.
Bundle sheath (BS) cells form a single cell layer surrounding the vascular tissue in leaves.
DOI: 10.1111/tpj.12470
The molecular basis of BS cell-fate specification remains unclear.
Certain transcription factors are expressed specifically in the BS cells and act redundantly in BS cell-fate specification, but their expression pattern and function diverge at later stages of leaf development.
http://onlinelibrary.wiley.com.....0/abstract
Cell fate control in the developing central nervous system
DOI: 10.1016/j.yexcr.2013.10.003
Highlights
• Similar mechanisms regulate cell fate in different CNS cell types and structures.
• Cell fate regulators operate in a spatial–temporal manner.
• Different neural cell types rely on the generation of a diversity of progenitor cells.
• Cell fate decision is dictated by the integration of intrinsic and extrinsic signals.
Abstract
The principal neural cell types forming the mature central nervous system (CNS) are now understood to be diverse.
This cellular subtype diversity originates to a large extent from the specification of the earlier proliferating progenitor populations during development.
Here, we review the processes governing the differentiation of a common neuroepithelial cell progenitor pool into mature neurons, astrocytes, oligodendrocytes, ependymal cells and adult stem cells.
We focus on studies performed in mice and involving two distinct CNS structures: the spinal cord and the cerebral cortex.
Understanding the origin, specification and developmental regulators of neural cells will ultimately impact comprehension and treatments of neurological disorders and diseases.
http://www.sciencedirect.com/s.....2713004205
Germ cell specification and pluripotency in mammals: a perspective from early embryogenesis
Germ cells are unique cell types that generate a totipotent zygote upon fertilization, giving rise to the next generation in mammals and many other multicellular organisms.
How germ cells acquire this ability has been of considerable interest.
In mammals, primordial germ cells (PGCs), the precursors of sperm and oocytes, are specified around the time of gastrulation.
PGCs are induced by signals from the surrounding extra-embryonic tissues to the equipotent epiblast cells that give rise to all cell types.
Currently, the mechanism of PGC specification in mammals is best understood from studies in mice.
Following implantation, the epiblast cells develop as an egg cylinder while the extra-embryonic ectoderm cells which are the source of important signals for PGC specification are located over the egg cylinder.
However, in most cases, including humans, the epiblast cells develop as a planar disc, which alters the organization and the source of the signaling for cell fates.
This, in turn, might have an effect on the precise mechanism of PGC specification in vivo as well as in vitro using pluripotent embryonic stem cells.
Here, we discuss how the key early embryonic differences between rodents and other mammals may affect the establishment of the pluripotency network in vivo and in vitro, and consequently the basis for PGC specification, particularly from pluripotent embryonic stem cells in vitro.
http://link.springer.com/artic.....014-0184-2
#376 gpuccio
I thank God for allowing an ignorant like me to find all these recent references to interesting scientific research papers that I can use in my current studies and also share with others in this blog.
Also I appreciate the help you provided with explaining some terminologies and concepts, as well as suggesting potential sources of information, when I started to ask what others considered dumb or silly questions.
Trying to understand the cell fate specification and determination mechanisms sometimes seems like resolving a huge complex puzzle, where many tiny pieces are all over a large table and many more are hidden somewhere out there beneath the night sky.
At this point a good friend of mine -who was my boss at work years ago- has suggested that I try this tool “Mind Meister” in order to map and organize the thoughts along with the reference materials in a way that is easier to access any required information. I’m starting to try using this tool.
That same friend has also suggested that I try hard to describe the ‘mysterious’ spatiotemporal mechanisms for cell fate specification, determination, differentiation and migration, in a way that is easier for nonscientists like my friend and myself to understand. I like his idea and am considering it very seriously now. However, this is a very difficult task for me.
Again, thank you for your encouraging comments. Maybe someday (Dios mediante) I can meet you personally to tell you: Mile grazie mio caro amico Dottore!
and then share a delicious Italian meal while singing:
Lasciatemi cantare con la chitarra in mano
Lasciatemi cantare una canzone piano piano
🙂
Now let’s get back to work.
Ciao!
Cell fate specification in the mammalian telencephalon
DOI: 10.1016/j.pneurobio.2007.02.009
A fundamental feature of neural development in vertebrates is that different cell types are generated in a precise temporal sequence, first neurons, followed by oligodendrocytes and astrocytes.
The mechanisms underlying these remarkable changes in progenitor fate during development are not well understood, but are thought to include both changes in the intrinsic properties of neural progenitors and changes in their signaling environment.
I discuss the mechanisms that control the specification of neuronal, astroglial and oligodendroglial fates, focusing on the mammalian telencephalon, one of the most extensively used models to study neural specification mechanisms in vertebrates.
I first consider the multiple extracellular signals that have been implicated in neural fate specification.
Their roles are often complex, with the same signals having different effects at different developmental stages, and different signaling pathways interacting extensively.
The selection of a particular cell fate ultimately results from the integration of multiple signals.
Signaling pathways regulate cell fates by modulating the expression and activity of numerous transcription factors in neural stem cells.
I discuss how transcription factors also act in a combinatorial manner to determine progenitor fates, with individual factors promoting the generation of one or two cell types and repressing alternative fate(s).
Finally, I discuss the many levels of regulation involved in preventing premature astrocyte differentiation during neurogenesis, and later on in controlling the transition from neurogenesis to gliogenesis.
http://www.sciencedirect.com/s.....8207000512
Signaling in Adult Brain Determines Neural Stem Cell (NSC)Positional Identity
the mechanism of adult NSC positional specification remains unknown
DOI: http://dx.doi.org/10.1016/j.neuron.2011.05.018
Signal explains why site of origin affects fate of postnatal neural stem cells
New research may help to explain why the location of postnatal neural stem cells in the brain determines the type of new neurons that are generated.
The research demonstrates that a signaling pathway which plays a key role in development also actively regulates the fate of neural stem cells in the adult brain.
http://www.sciencedaily.com/re.....121550.htm
Researchers apply brainpower to understanding neural stem cell differentiation
Researchers explain how neural stem and progenitor cells differentiate into neurons and related cells called glia.
Neural stem and progenitor cells offer tremendous promise as a future treatment for neurodegenerative disorders, and understanding their differentiation is the first step towards harnessing this therapeutic potential.
http://www.sciencedaily.com/re.....121450.htm
Relative quiescence and self renewal are defining features of adult stem cells, but their potential coordination remains unclear.
doi:10.1038/nn.3545
http://www.nature.com/neuro/jo......3545.html
Maintenance mechanism prevents stem cells from aging
research may shed light on the maintenance of stem cells in the adult brain, and their activity to produce new neurons throughout life.
http://www.sciencedaily.com/re.....091553.htm
Embryonic stem cell identity grounded in the embryo
doi:10.1038/ncb2984
Pluripotent embryonic stem cells (ESCs) can be derived from blastocyst-stage mouse embryos.
However, the exact in vivo counterpart of ESCs has remained elusive.
A combination of expression profiling and stem cell derivation identifies epiblast cells from late-stage blastocysts as the source, and functional equivalent, of ESCs.
http://www.nature.com/ncb/jour.....b2984.html
NIH Single Cell Analysis Challenge: Follow That Cell
Many biological experiments are performed under the assumption that all cells of a particular “type” are identical.
However, recent data suggest that individual cells within a single population may differ quite significantly and these differences can drive the health and function of the entire cell population.
Single cell analysis comprises a broad field that covers advanced optical, electrochemical, mass spectrometry instrumentation, and sensor technology, as well as separation and sequencing techniques.
Although the approaches currently in use can offer snapshots of single cells, the methods are often not amenable to longitudinal studies that monitor changes in individual cells in situ.
https://www.innocentive.com/ar/challenge/9933618?cc=Nature9933618&utm_source=nature&utm_medium=pavilion&utm_campaign=challenges
Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport
doi:10.1038/ncb3029
Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues.
Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood.
http://www.nature.com/ncb/jour.....b3029.html
The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification
doi:10.1038/ncb2965
The precise relationship of embryonic stem cells (ESCs) to cells in the embryo remains controversial.
We present transcriptional and functional data to identify the embryonic counterpart of ESCs.
Marker profiling shows that ESCs are distinct from early inner cell mass (ICM) and closely resemble pre-implantation epiblast.
A characteristic feature of mouse ESCs is propagation without ERK signalling.
Single-cell culture reveals that cell-autonomous capacity to thrive when the ERK pathway is inhibited arises late during blastocyst development and is lost after implantation.
The frequency of deriving clonal ESC lines suggests that all E4.5 epiblast cells can become ESCs.
We further show that ICM cells from early blastocysts can progress to ERK independence if provided with a specific laminin substrate.
These findings suggest that formation of the epiblast coincides with competence for ERK-independent self-renewal in vitro and consequent propagation as ESC lines.
http://www.nature.com/ncb/jour.....b2965.html
Mitotic spindle multipolarity without centrosome amplification
doi:10.1038/ncb2958
Mitotic spindle bipolarity is essential for faithful segregation of chromosomes during cell division.
Multipolar spindles are often seen in human cancers and are usually associated with supernumerary centrosomes that result from centrosome overduplication or cytokinesis failure.
A less-understood path to multipolar spindle formation may arise due to loss of spindle pole integrity in response to spindle and/or chromosomal forces.
Here we discuss the different routes leading to multipolar spindle formation, focusing on spindle multipolarity without centrosome amplification.
We also present the distinct and common features between these pathways and discuss their therapeutic implications.
http://www.nature.com/ncb/jour.....b2958.html
The biogenesis of chromosome translocations
doi:10.1038/ncb2941
Chromosome translocations are catastrophic genomic events and often play key roles in tumorigenesis.
Yet the biogenesis of chromosome translocations is remarkably poorly understood.
Recent work has delineated several distinct mechanistic steps in the formation of translocations, and it has become apparent that non-random spatial genome organization, DNA repair pathways and chromatin features, including histone marks and the dynamic motion of broken chromatin, are critical for determining translocation frequency and partner selection.
http://www.nature.com/ncb/jour.....b2941.html
Sliding filaments and mitotic spindle organization
doi:10.1038/ncb3019
Mitosis depends upon the action of the mitotic spindle, a subcellular machine that uses microtubules (MTs) and motors to assemble itself and to coordinate chromosome segregation.
Recent work illuminates how the motor-driven poleward sliding of MTs — nucleated at centrosomes, chromosomes and on pre-existing MTs — contributes to spindle assembly and length control.
http://www.nature.com/ncb/jour.....b3019.html
The dynamics of microtubule minus ends in the human mitotic spindle
doi:10.1038/ncb2996
During mitotic spindle assembly, ?-tubulin ring complexes (?TuRCs) nucleate microtubules at centrosomes, around chromosomes, and, by interaction with augmin, from pre-existing microtubules.
How different populations of microtubules are organized to form a bipolar spindle is poorly understood, in part because we lack information on the dynamics of microtubule minus ends.
Here we show that ?TuRC is associated with minus ends of non-centrosomal spindle microtubules.
Recruitment of ?TuRC to spindles occurs preferentially at pole-distal regions, requires nucleation and/or interaction with minus ends, and is followed by sorting of minus-end-bound ?TuRC towards the poles.
Poleward movement of ?TuRC exceeds k-fibre flux, involves the motors dynein, ?HSET (also known as ?KIFC1; a kinesin-14 family member) and ?Eg5 (also known as ?KIF11; a kinesin-5 family member), and slows down in pole-proximal regions, resulting in the accumulation of minus ends.
Thus, in addition to nucleation, ?TuRC actively contributes to spindle architecture by organizing microtubule minus ends.
http://www.nature.com/ncb/jour.....b2996.html
Towards elucidating the tubulin code
doi:10.1038/ncb2938
Genetically encoded and post-translationally generated variations of tubulin C-terminal tails give rise to extensive heterogeneity of the microtubule cytoskeleton.
The generation of different tubulin variants now demonstrates how single amino-acid differences or post-translational modifications can modulate the behaviour of selected molecular motors.
http://www.nature.com/ncb/jour.....b2938.html
Regulation of microtubule motors by tubulin isotypes and post-translational modifications
doi:10.1038/ncb2920
The ‘tubulin-code’ hypothesis proposes that different tubulin genes or post-translational modifications (PTMs), which mainly confer variation in the carboxy-terminal tail (CTT), result in unique interactions with microtubule-associated proteins for specific cellular functions.
However, the inability to isolate distinct and homogeneous tubulin species has hindered biochemical testing of this hypothesis.
tubulin isotypes and PTMs can govern motor velocity, processivity and microtubule depolymerization rates, with substantial changes conferred by even single amino acid variation.
different molecular motors recognize distinctive tubulin ‘signatures’, which supports the premise of the tubulin-code hypothesis.
http://www.nature.com/ncb/jour.....b2920.html
The tubulin code: Molecular components, readout mechanisms, and functions
doi: 10.1083/jcb.201406055
Microtubules are cytoskeletal filaments that are dynamically assembled from ?/?-tubulin heterodimers.
The primary sequence and structure of the tubulin proteins and, consequently, the properties and architecture of microtubules are highly conserved in eukaryotes.
Despite this conservation, tubulin is subject to heterogeneity that is generated in two ways: by the expression of different tubulin isotypes and by posttranslational modifications (PTMs).
Identifying the mechanisms that generate and control tubulin heterogeneity and how this heterogeneity affects microtubule function are long-standing goals in the field.
Recent work on tubulin PTMs has shed light on how these modifications could contribute to a “tubulin code” that coordinates the complex functions of microtubules in cells.
http://jcb.rupress.org/content/206/4/461
The Code of codes
At one level,
the human body
is an Enigma–
a code machine.
All day long they run:
informing,
creating,
conducting.
There’s the genetic code, sure.
Then there’s
the histone code,
the sugar code,
the signal transduction code,
the ubiquitin code,
the adhesive code,
the splicing code,
the tubulin code,
the metabolic code,
and so on and so forth.
Michael Mark’s blog:
http://embracingforever.com/20.....rist-code/
Structural basis for microtubule recognition by the human kinetochore Ska complex
doi:10.1038/ncomms3964
The ability of kinetochores (KTs) to maintain stable attachments to dynamic microtubule structures (‘straight’ during microtubule polymerization and ‘curved’ during microtubule depolymerization) is an essential requirement for accurate chromosome segregation.
Here we show that the kinetochore-associated Ska complex interacts with tubulin monomers via the carboxy-terminal winged-helix domain of Ska1, providing the structural basis for the ability to bind both straight and curved microtubule structures.
This contrasts with the Ndc80 complex, which binds straight microtubules by recognizing the dimeric interface of tubulin.
The Ska1 microtubule-binding domain interacts with tubulins using multiple contact sites that allow the Ska complex to bind microtubules in multiple modes.
Disrupting either the flexibility or the tubulin contact sites of the Ska1 microtubule-binding domain perturbs normal mitotic progression, explaining the critical role of the Ska complex in maintaining a firm grip on dynamic microtubules.
http://www.nature.com/ncomms/2.....s3964.html
A blueprint for kinetochores — new insights into the molecular mechanics of cell division
doi:10.1038/nrm3133
Kinetochores are large proteinaceous complexes that physically link centromeric DNA to the plus ends of spindle microtubules.
Stable kinetochore–microtubule attachments are a prerequisite for the accurate and efficient distribution of genetic material over multiple generations.
In the past decade, concerted research has resulted in the identification of the individual kinetochore building blocks, the characterization of critical microtubule-interacting components, such as the NDC80 complex, and the development of an approximate model of the architecture of this sophisticated biological machine.
http://www.nature.com/nrm/jour.....m3133.html
Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint
doi:10.1038/ncomms5795
The spindle assembly checkpoint arrests mitotic progression until each kinetochore secures a stable attachment to the spindle.
Despite fluctuating noise, this checkpoint remains robust and remarkably sensitive to even a single unattached kinetochore among many attached kinetochores; moreover, the checkpoint is silenced only after the final kinetochore-spindle attachment.
Experimental observations have shown that checkpoint components stream from attached kinetochores along microtubules towards spindle poles.
Here we incorporate this streaming behavior into a theoretical model that accounts for the robustness of checkpoint silencing.
Poleward streams are integrated at spindle poles, but are diverted by any unattached kinetochore; consequently, accumulation of checkpoint components at spindle poles increases markedly only when every kinetochore is properly attached.
This step change robustly triggers checkpoint silencing after, and only after, the final kinetochore-spindle attachment.
Our model offers a conceptual framework that highlights the role of spatiotemporal regulation in mitotic spindle checkpoint signaling and fidelity of chromosome segregation.
http://www.nature.com/ncomms/2.....s5795.html
Microtubule attachment and spindle assembly checkpoint signalling at the kinetochores
doi:10.1038/nrm3494
In eukaryotes, chromosome segregation during cell division is facilitated by the kinetochore, a multiprotein structure that is assembled on centromeric DNA.
The kinetochore attaches chromosomes to spindle microtubules, modulates the stability of these attachments and relays the microtubule-binding status to the spindle assembly checkpoint (SAC), a cell cycle surveillance pathway that delays chromosome segregation in response to unattached kinetochores.
Recent studies are shaping current thinking on how each of these kinetochore-centred processes is achieved, and how their integration ensures faithful chromosome segregation, focusing on the essential roles of kinase–phosphatase signalling and the microtubule-binding KMN protein network.
http://www.nature.com/nrm/jour.....m3494.html
Kinetochore: Structure, Function
DOI: 10.1002/9780470015902.a0006237.pub2
Duplicated eukaryotic chromosomes are segregated into daughter cells through cell division.
Faithful chromosome segregation depends on kinetochores, which are specialized macromolecular structures built upon centromeric chromatin.
The dynamic kinetochore structures connect chromosomes with spindle microtubules, power chromosome movement, and signal the activation and silencing of the spindle assembly checkpoint (SAC).
Molecular analyses of the components and architecture of kinetochores have advanced rapidly in recent years.
A human kinetochore contains approximately 200 proteins, many of which are evolutionarily conserved in other organisms.
A histone H3 variant, CENP?A and associated constitutive centromere proteins lay the foundation for kinetochore build?up. Multiple kinetochore?localised microtubule?binding proteins including the Ndc80 complex help regulate chromosome movement.
The SAC signalling originates from kinetochores and contributes to the fidelity of chromosome segregation.
Many fascinating properties remain to be elucidated about the kinetochore as a fundamental machinery to maintain genomic stability.
Key Concepts:
•Chromosome segregation in eukaryotic cells depends upon connecting spindle microtubules with special macromolecular structures on chromosomes called kinetochores.
•The centromere is the chromosomal locus where a kinetochore is built.
•Laying the foundation for kinetochore assembly at centromeres are CENP?A (a histone H3 variant) containing nucleosomes and a group of CENP?A associated proteins (termed constitutive centromere proteins).
•There are multiple microtubule motors and nonmotor microtubule?binding proteins localised at kinetochores to coordinate chromosome movement.
•A 10 protein complex called KMN network is currently thought to provide the primary end?on microtubule?binding activity.
•The spindle assembly checkpoint (SAC) monitors the kinetochore–microtubule attachment and signals the delay of the metaphase?to?anaphase transition when defects are detected.
•Conformational change of MAD2 and assembly of the mitotic checkpoint complex (MCC) are the key events to activate the SAC.
•Comparative studies of similar and distinct kinetochore composition, structure and function in different species and during mitosis or meiosis have provided evolutionary perspectives on mechanisms regulating chromosome segregation.
http://www.els.net/WileyCDA/El.....06237.html
The Kinetochore
doi: 10.1101/cshperspect.a015826
A critical requirement for mitosis is the distribution of genetic material to the two daughter cells.
The central player in this process is the macromolecular kinetochore structure, which binds to both chromosomal DNA and spindle microtubule polymers to direct chromosome alignment and segregation.
This review will discuss the key kinetochore activities required for mitotic chromosome segregation, including the recognition of a specific site on each chromosome, kinetochore assembly and the formation of kinetochore–microtubule connections, the generation of force to drive chromosome segregation, and the regulation of kinetochore function to ensure that chromosome segregation occurs with high fidelity.
http://cshperspectives.cshlp.o.....6.abstract
Dynamics of the DNA damage response: insights from live-cell imaging
Briefings in Functional Genomics (2013)
12 (2): 109-117.
doi: 10.1093/bfgp/els059
All organisms have to safeguard the integrity of their genome to prevent malfunctioning and oncogenic transformation.
Sophisticated DNA damage response mechanisms
have evolved todetect and repair genomic lesions.With the emergence of live-cell microscopy of individual cells, we now begin to appreciate the complex spatiotemporal kinetics of the DNA damage response and can address the causes and consequences of the heterogeneity in the responses of genetically identical cells.
Here, we highlight key discoveries where live-cell imaging has provided unprecedented insights into how cells respond to DNA double-strand breaks and discuss the main challenges and promises in using this technique.
http://bfg.oxfordjournals.org/.....541ef81a34
DNA anaphase bridges are a potential source of genome instability that may lead to chromosome breakage or nondisjunction during mitosis
doi: 10.1083/jcb.201305157
TopBP1/Dpb11 prevents accumulation of anaphase bridges via stimulation of the Mec1/ATR kinase and suppression of homologous recombination.
http://jcb.rupress.org/content.....02de12ee3e
Sending sisters their separate ways
Repair protein helps resolve entanglements between sister chromatids
doi: 10.1083/jcb.2041if
Sister chromatids are often reluctant to separate during mitosis, but apparently a protein involved in DNA replication and repair helps eliminate lingering connections that can hold sister chromatids together.
http://jcb.rupress.org/content/204/1/3.full
I love this thread Dio. Thank You.
Upright BiPed
Glad to know you like it! 🙂
I’m just posting links to interesting papers.
Anyone could do this.
Thank God that I can do it too. 🙂
This is a fascinating time to watch what’s going on in serious biological research.
I’m attracted to understanding cell fate specification and determination mechanisms, from a functional information processing perspective. That includes the elaborate choreographies found in the intrinsic asymmetric mitosis.
This is why many posts in this thread have to do with this subject.
However, I’m also interested in other related biological processes.
Now, don’t forget to constantly remind yourself that all these wonderful things we observe are the product of the powerful magic ‘n-D e’ formula RV+NS+T! Agree? 😉
Kinetochores require oligomerization of Dam1 complex to maintain microtubule attachments against tension and promote biorientation
doi:10.1038/ncomms5951
Kinetochores assemble on centromeric DNA and present arrays of proteins that attach directly to the dynamic ends of microtubules.
Kinetochore proteins coordinate at the microtubule interface through oligomerization, but how oligomerization contributes to kinetochore function has remained unclear.
Here, using a combination of biophysical assays and live-cell imaging, we find that oligomerization of the Dam1 complex is required for its ability to form microtubule attachments that are robust against tension in vitro and in vivo.
An oligomerization-deficient Dam1 complex that retains wild-type microtubule binding activity is primarily defective in coupling to disassembling microtubule ends under mechanical loads applied by a laser trap in vitro.
In cells, the oligomerization-deficient Dam1 complex is unable to support stable bipolar alignment of sister chromatids, indicating failure of kinetochore–microtubule attachments under tension.
We propose that oligomerization is an essential and conserved feature of kinetochore components that is required for accurate chromosome segregation during mitosis.
http://www.nature.com/ncomms/2.....s5951.html
The human centromere/kinetochore complex
http://www.fli-leibniz.de/grou....._hk_en.php
Interaction of the mitotic checkpoint complex (MCC) with the anaphase promoting complex/cyclosome (APC/C)
http://www.fli-leibniz.de/grou.....ion_en.php
The dynamic kinetochore-microtubule interface
http://jcs.biologists.org/cont......large.jpg
Shugoshin biases chromosomes for biorientation through condensin recruitment to the pericentromere
During cell division the chromosomes line up in a way that increases the chances that the daughter cells will each inherit one copy of each chromosome after cell division.
This study shows that proteins known as shugoshins assemble a “hub” on a region of the DNA called the pericentromere that monitors the lining up of chromosome for accurate cell division.
http://www.wcb.ed.ac.uk/paper/.....centromere
A transcriptome-wide atlas of RNP composition reveals diverse classes of mRNAs and lncRNAs
A transcriptome-wide analysis shows that different classes of mRNAs and lncRNAs are characterized by distinct mechanisms of 3? end formation and RNP complexes, explaining how cells distinguish among these otherwise similar RNAs.
http://www.wcb.ed.ac.uk/paper/.....nd-lncrnas
Structural and functional elements of the centromere region
The centromere/inner kinetochore, outer kinetochore, centric heterochromatin and chromosome arms, and associated functions, are shown.
http://www.nature.com/nrg/jour.....4a_F1.html
Enhancing togetherness: kinetochores and cohesion
Kinetochore–microtubule attachments.
Chromosomes are shown in blue, centromeres in yellow, microtubules in black, and spindle poles in green.
(A) Amphitelic attachment: Each kinetochore is attached to microtubules from opposing spindle poles.
(B) Syntelic attachment: Both sister kinetochores are attached to microtubules from the same spindle pole.
(C) Monotelic attachment: One kinetochore is attached to a microtubule from a spindle pole and the other kinetochore is not attached to a microubule.
(D) Activation of the spindle checkpoint can occur via a tension defect or an attachment defect.
http://genesdev.cshlp.org/cont......large.jpg
epigenetic mediator expression and function in embryonic blastomeres
doi: 10.1093/hmg/ddu212
A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications.
Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation.
We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level.
In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage.
Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture.
Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation.
Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development.
http://hmg.oxfordjournals.org/.....f7063022fb
mitosis and mitotic spindle organization
doi: 10.1093/hmg/ddt436
Heterozygous LIS1 mutations are responsible for the human neuronal migration disorder lissencephaly.
Mitotic functions of LIS1 have been suggested from many organisms throughout evolution.
However, the cellular functions of LIS1 at distinct intracellular compartments such as the centrosome and the cell cortex have not been well defined especially during mitotic cell division.
Here, we used detailed cellular approaches and time-lapse live cell imaging of mitosis from Lis1 mutant mouse embryonic fibroblasts to reveal critical roles of LIS1 in mitotic spindle regulation.
We found that LIS1 is required for the tight control of chromosome congression and segregation to dictate kinetochore–microtubule (MT) interactions and anaphase progression.
In addition, LIS1 is essential for the establishment of mitotic spindle pole integrity by maintaining normal centrosome number.
Moreover, LIS1 plays crucial roles in mitotic spindle orientation by increasing the density of astral MT plus-end movements toward the cell cortex, which enhances cortical targeting of LIS1–dynein complex.
Overexpression of NDEL1–dynein and MT stabilization rescues spindle orientation defects in Lis1 mutants, demonstrating that mouse LIS1 acts via the LIS1–NDEL1–dynein complex to regulate astral MT plus-ends dynamics and establish proper contacts of MTs with the cell cortex to ensure precise cell division.
http://hmg.oxfordjournals.org/.....f7063022fb
spindle orientation and neurogenesis
doi: 10.1242/?bio.20147807
Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions.
The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types.
[…] we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis.
We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation.
Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons.
These Pax6-positive aNPs display a tilted mitotic spindle.
In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly.
We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.
http://bio.biologists.org/content/3/6/475.abstract
Regulation of pre-mRNA alternative splicing
DOI: http://dx.doi.org/10.1182/blood-2013-12-542209
The scope and roles of regulated isoform gene expression during erythroid terminal development are poorly understood.
We identified hundreds of differentiation-associated isoform changes during terminal erythropoiesis.
Sequences surrounding cassette exons of skipped exon events are enriched for motifs bound by the Muscleblind-like (MBNL) family of splicing factors.
Knockdown of Mbnl1 in cultured murine fetal liver erythroid progenitors resulted in a strong block in erythroid differentiation and disrupted the developmentally regulated exon skipping of Ndel1 mRNA, which is bound by MBNL1 and critical for erythroid terminal proliferation.
These findings reveal an unanticipated scope of the alternative splicing program and the importance of Mbnl1 during erythroid terminal differentiation.
http://www.bloodjournal.org/co.....8.abstract
ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes
doi: 10.1101/gad.246579.114
Genes & Dev. 2014. 28: 2013-2026
ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis.
How ZNF750 accomplishes these dual gene regulatory impacts is unknown.
Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif.
ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences.
ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes ?10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression.
In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.
http://genesdev.cshlp.org/cont.....6cc7782dcf
New technique reveals a role for histones in cell division
Proteins known as histones give structure to DNA, which coils around them like string on spools.
But as is so often the case in biology, it turns out there is more to these structures than meets the eye.
Scientists already know histones play a part in controlling the expression of genes, and more recently they have accumulated evidence that certain aspects of cell division depend on these proteins.
But this last suspicion has proven difficult to test.
Now a new technique developed at Rockefeller University in Hironori Funabiki’s Laboratory of Chromosome and Cell Biology allows researchers to examine histones’ role in crucial cell division processes that revolve around DNA, such as the segregation of chromosomes and the construction of the cell’s nucleus.
Hooray for histones: Researchers found that beads covered with histones and DNA (top) attracted a protein called lamin B3 (green) that supports the membrane around a new cell’s nucleus.
Beads with only DNA (bottom) did not attract lamins.
http://phys.org/news/2014-09-t.....-cell.html
Cells simply avoid chromosome confusion: Reproductive cell division has a mechanical safeguard against errors
Reproductive cell division has evolved a simple, mechanical solution to avoid chromosome sorting errors, researchers report in the Sept. 11 Science Express.
This natural safeguard prevents incorrect chromosome counts and misalignments that lead to infertility, miscarriage, or congenital conditions.
Meiosis occurs, for example, to create sperm or egg cells. The reduction allows offspring to inherit half their chromosomes from their father, and half from their mother.
“During cell division, chromosomes must be precisely sorted in an elaborate choreography where chromosomes pair up and then part in a sequence.”
However, the arrangement gets complicated during the early stages of reproductive cell division. Instead of just pairs of chromosomes, the spindle-like apparatus in cells that pulls chromosomes apart has to deal with quartets.
Each contains two ‘sister chromatids’ coming from the mother linked to two coming from the father A chromatid is either of the two strands formed when a chromosome is duplicated; sister chromatids are identical copies.
http://phys.org/news/2014-09-c.....-cell.html
Faithful cell division requires tightly controlled protein placement at the centromeres
From fertilized egg to adult, the cells of the human body go through an astronomical number of divisions.
During division of any of the body’s roughly 30 trillion cells, DNA from the initial cell must be split precisely between the two resulting cells.
Critical to successful cell division is the integrity of the centromere—a region of DNA on each chromosome where the cell division machinery attaches to segregate the chromosomes.
http://phys.org/news/2014-07-f.....ghtly.html
What makes cell division accurate?
Cell division is helped along by a complex of more than 90 proteins, called a kinetochore, interacting with scaffolding-like structural fibers called microtubules.
Together the kinetochore and microtubules provide the structure and force that pull the two duplicate halves of the chromosome apart and direct them to each daughter cell.
The study of mitosis has focused on microtubules and kinetochores, the most prominent structure that researchers observe.
This work demonstrates the importance of expanding the scope of study to include other cellular components because this is critical to achieving an in depth understanding of the mechanisms underlying chromosome alignment in preparation for dividing the DNA into two new cells
http://phys.org/news/2014-01-c.....urate.html
The machinery of mitosis: Kinetechores, centrioles and chromosome pumps
At the cellular level, the mitotic spindle apparatus is arguably the most complicated piece of machinery in existence.
Its basic function is to isolate and separate the chromosomes during cell division.
A group of researchers at the University of North Carolina have been piecing together a model of the spindle and associated proteins which provides a way to visualize in detail exactly what might be going on.
The group chose to simulate budding yeast cells because their entire spindle is comprised of only around 40 microtubules (MTs), compared to 100 times that amount in mammalian cells.
Over the years the group has contributed to an emerging mechanical picture of the spindle wherein the MTs provide the compression elements, pericentric chromatin the elastic tension elements, and a proteinaceous kinetochore bridges the two polymers together.
Their most recent paper, published in Current Biology, provides a new and detailed 3d map of the kinetochore region of the chromosome, and seeks to provides answers to the origins of the seemingly mysterious force that organizes the dividing cell.
http://phys.org/news/2013-10-m.....osome.html
Secretory cargo sorting at the trans-Golgi network
DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.007
Sorting of proteins for secretion from cells is crucial for normal physiology and the regulation of key cellular events.
Although the sorting of lysosomal hydrolases at the trans-Golgi network (TGN) for delivery to pre-lysosomes is well characterized, the corresponding mechanism by which secreted proteins are sorted for plasma-membrane delivery remains poorly understood.
Recent discoveries have revealed a novel sorting mechanism that requires the linkage between the cytoplasmic actin cytoskeleton to the membrane-anchored Ca2+ ATPase, SPCA1 (secretory pathway calcium ATPase 1), and the luminal 45?kDa Ca2+-binding protein, Cab45, for successful sorting of a subset of proteins at the TGN.
We review progress in understanding these processes.
http://www.cell.com/trends/cel.....ll%20Press
Physiological roles of long noncoding RNAs
DOI: http://dx.doi.org/10.1016/j.tcb.2014.06.003
Long noncoding RNAs (lncRNAs) are a pervasive and recently recognized class of genes.
lncRNAs have been proposed to modulate gene expression and nuclear architecture, but their physiological functions are still largely unclear.
Several recent efforts to inactivate lncRNA genes in mouse models have shed light on their functions.
Different genetic strategies have yielded specific lessons about the roles of lncRNA transcription, the lncRNA transcript itself, and underlying sequence elements.
Current results indicate important functions #for lncRNAs in organ development, immunity, organismal viability, and in human diseases.
http://www.cell.com/trends/cel.....all%3Dtrue
LIM proteins in actin cytoskeleton mechanoresponse
DOI: http://dx.doi.org/10.1016/j.tcb.2014.04.009
The actin cytoskeleton assembles into branched networks or bundles to generate mechanical force for critical cellular processes such as establishment of polarity, adhesion, and migration.
Stress fibers (SFs) are contractile actomyosin structures that physically couple to the extracellular matrix through integrin-based focal adhesions (FAs), thereby transmitting force into and across the cell.
Recently, LIN-11, Isl1, and MEC-3 (LIM) domain proteins have been implicated in mediating this cytoskeletal mechanotransduction.
Among the more well-studied LIM domain adapter proteins is zyxin, a dynamic component of both FAs and SFs.
Here we discuss recent research detailing the mechanisms by which SFs adjust their structure and composition to balance mechanical forces and suggest ways that zyxin and other LIM domain proteins mediate mechanoresponse.
http://www.cell.com/trends/cel.....ll%20Press
An agent-based model for mRNA export through the nuclear pore complex
doi: 10.1091/mbc.E14-06-1065
mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood.
The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known.
It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the NPC.
Using previously published biophysical and biochemical parameters of mRNA export, we implemented a 3D coarse-grained agent- based model of mRNA export in the nanosecond regime to gain insight into these questions.
On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA, and that there is a rate- limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel.
Notably, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport.
This has implications for future experimental design to study mRNA transport dynamics.
http://www.molbiolcell.org/con.....ab2fc7bad6
Making the spindle checkpoint strong
doi:10.1038/nrm3828
Spindle checkpoint signals (generated by checkpoint proteins) arrest mitosis until all kinetochores are correctly attached to spindle microtubules, whereupon checkpoint proteins are removed in a dynein-dependent manner.
http://www.nature.com/nrm/jour.....m3828.html
I too hold the view that both ID and Evolution are inadequate in explaining origin of life and evolution of various species. The 3rd explanation is not satisfactory either. I think we may never know how life started and spread. It is a futile search.
#438 the bystander
But we could benefit from knowing well how this complex stuff works. Most serious biology scientists study current mechanisms, current structures, not OOL. They are too busy trying to figure out how things work, hence don’t have time to think about OOL issues.
To Christians, the OOL discussion is irrelevant, because, although we don’t know how it happened, we know the agent.
ID proponents in general don’t know who the design agent is. That question is not part of ID.
Anyway, it is fascinating to study this puzzle.
🙂
Myosin VIII associates with microtubule ends and together with actin plays a role in guiding plant cell division
DOI: http://dx.doi.org/10.7554/eLife.03498
Plant cells divide using the phragmoplast, a microtubule-based structure that directs vesicles secretion to the nascent cell plate.
The phragmoplast forms at the cell center and expands to reach a specified site at the cell periphery, tens or hundreds of microns distant.
The mechanism responsible for guiding the phragmoplast remains largely unknown.
Here, using both moss and tobacco, we show that myosin VIII associates with the ends of phragmoplast microtubules and together with actin plays a role in guiding phragmoplast expansion to the cortical division site.
Our data lead to a model whereby myosin VIII links phragmoplast microtubules to the cortical division site via actin filaments.
Myosin VIII’s motor activity along actin provides a molecular mechanism for steering phragmoplast expansion.
http://elifesciences.org/conte.....abstract-1
A molecular mechanism of mitotic centrosome assembly
DOI: http://dx.doi.org/10.7554/eLife.03399
Centrosomes comprise a pair of centrioles surrounded by pericentriolar material (PCM).
The PCM expands dramatically as cells enter mitosis, but it is unclear how this occurs.
In this study, we show that the centriole protein Asl initiates the recruitment of DSpd-2 and Cnn to mother centrioles; both proteins then assemble into co-dependent scaffold-like structures that spread outwards from the mother centriole and recruit most, if not all, other PCM components.
In the absence of either DSpd-2 or Cnn, mitotic PCM assembly is diminished; in the absence of both proteins, it appears to be abolished.
We show that DSpd-2 helps incorporate Cnn into the PCM and that Cnn then helps maintain DSpd-2 within the PCM, creating a positive feedback loop that promotes robust PCM expansion around the mother centriole during mitosis.
These observations suggest a surprisingly simple mechanism of mitotic PCM assembly in flies. –
See more at: http://elifesciences.org/conte.....3AWaS.dpuf
#438 the bystander
The belief that the design agent of OOL is the God of the Bible is not provided by science, including ID, but by God Himself through His special revelation (His word). Nature is God’s general revelation. It makes us wonder, for example it makes ID proponents wonder about the origin of functional complex specified information. But it does not reveal the many details about God that we find in the Bible.
Garbage In = Garbage Out? Complex Biological Sample Preparation for Omics Studies
http://www.genengnews.com/webi.....udies/232/
Unraveling cell division: Process of mitosis more clear, thanks to new research
At this very moment thousands of our body’s cells are duplicating and dividing.
This is the mechanism by which the body repairs damaged tissues and regenerates others like skin and hair.
It involves a fairly complex process known as “mitosis,” during which the cell duplicates its genetic material and separates it into two identical halves, which are then split apart.
It is crucially important that this process works well each and every time it takes place, as otherwise it could give rise to mutations that might trigger diseases such as cancer.
http://www.sciencedaily.com/re.....101958.htm
Chromosome length and perinuclear attachment constrain resolution of DNA intertwines
doi: 10.1083/jcb.201404039
To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication.
How this process extends to the full genome is not well understood.
In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase.
In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II–dependent segregation.
Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells.
Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes.
Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope.
We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase.
http://jcb.rupress.org/content/206/6/719
spindle assembly checkpoint silencing
doi: 10.1083/jcb.201406109
The spindle assembly checkpoint (SAC) monitors correct attachment of chromosomes to microtubules, an important safeguard mechanism ensuring faithful chromosome segregation in eukaryotic cells.
How the SAC signal is turned off once all the chromosomes have successfully attached to the spindle remains an unresolved question.
Mps1 phosphorylation of Knl1 results in recruitment of the SAC proteins Bub1, Bub3, and BubR1 to the kinetochore and production of the wait-anaphase signal.
SAC silencing is therefore expected to involve a phosphatase opposing Mps1.
Here we demonstrate in vivo and in vitro that BubR1-associated PP2A-B56 is a key phosphatase for the removal of the Mps1-mediated Knl1 phosphorylations necessary for Bub1/BubR1 recruitment in mammalian cells.
SAC silencing is thus promoted by a negative feedback loop involving the Mps1-dependent recruitment of a phosphatase opposing Mps1.
Our findings extend the previously reported role for BubR1-associated PP2A-B56 in opposing Aurora B and suggest that BubR1-bound PP2A-B56 integrates kinetochore surveillance and silencing of the SAC.
http://jcb.rupress.org/content.....b69b5d83c0
Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II
[Say what?] 🙂
In mitosis, the Greatwall kinase (called microtubule-associated serine/threonine kinase like [Mastl] in mammals) is essential for prometaphase entry or progression by suppressing protein phosphatase 2A (PP2A) activity.
PP2A suppression in turn leads to high levels of Cdk1 substrate phosphorylation.
We have used a mouse model with an oocyte-specific deletion of Mastl to show that Mastl-null oocytes resume meiosis I and reach metaphase I normally but that the onset and completion of anaphase I are delayed.
Moreover, after the completion of meiosis I, Mastl-null oocytes failed to enter meiosis II (MII) because they reassembled a nuclear structure containing decondensed chromatin.
Our results show that Mastl is required for the timely activation of anaphase-promoting complex/cyclosome to allow meiosis I exit and for the rapid rise of Cdk1 activity that is needed for the entry into MII in mouse oocytes.
doi: 10.1083/jcb.201406033
http://jcb.rupress.org/content.....b69b5d83c0
Enzyme helps fold the spindle assembly checkpoint (SAC)
doi: 10.1083/jcb.2067iti1
phosphatase that helps shut down the spindle assembly checkpoint (SAC) when chromosomes are correctly attached to the spindle.
The SAC prevents cells from entering anaphase until they have verified the connections between spindle microtubules and the chromosomes.
The checkpoint forms when the enzyme Mps1 phosphorylates the kinetochore protein Knl1, and this alteration attracts other SAC proteins such as Bub1 and BubR1 to kinetochores.
Once all the chromosome–spindle links check out, cells remove the phosphates from Knl1, and the checkpoint shuts down as Bub1 and other components disperse.
In yeast, the phosphatase PP1, a member of the phosphoprotein phosphatase (PPP) family, dephosphorylates Knl1, but researchers weren’t sure which enzyme performs the task in mammalian cells.
http://jcb.rupress.org/content.....b69b5d83c0
Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival
doi: 10.1083/jcb.201402002
Unless mitigated, external and physiological stresses are detrimental for cells, especially in mitosis, resulting in chromosomal missegregation, aneuploidy, or apoptosis.
Heat shock proteins (Hsps) maintain protein homeostasis and promote cell survival.
Hsps are transcriptionally regulated by heat shock factors (HSFs).
Of these, HSF1 is the master regulator and HSF2 modulates Hsp expression by interacting with HSF1.
Due to global inhibition of transcription in mitosis, including HSF1-mediated expression of Hsps, mitotic cells are highly vulnerable to stress.
Here, we show that cells can counteract transcriptional silencing and protect themselves against proteotoxicity in mitosis.
We found that the condensed chromatin of HSF2-deficient cells is accessible for HSF1 and RNA polymerase II, allowing stress-inducible Hsp expression.
Consequently, HSF2-deficient cells exposed to acute stress display diminished mitotic errors and have a survival advantage.
We also show that HSF2 expression declines during mitosis in several but not all human cell lines, which corresponds to the Hsp70 induction and protection against stress-induced mitotic abnormalities and apoptosis.
http://jcb.rupress.org/content.....b69b5d83c0
Dlg1 controls planar spindle orientation in the neuroepithelium through direct interaction with LGN
doi: 10.1083/jcb.201405060
Oriented cell divisions are necessary for the development of epithelial structures.
Mitotic spindle orientation requires the precise localization of force generators at the cell cortex via the evolutionarily conserved LGN complex.
However, polarity cues acting upstream of this complex in vivo in the vertebrate epithelia remain unknown.
In this paper, we show that Dlg1 is localized at the basolateral cell cortex during mitosis and is necessary for planar spindle orientation in the chick neuroepithelium.
Live imaging revealed that Dlg1 is required for directed spindle movements during metaphase.
Mechanistically, we show that direct interaction between Dlg1 and LGN promotes cortical localization of the LGN complex.
Furthermore, in human cells dividing on adhesive micropatterns, homogenously localized Dlg1 recruited LGN to the mitotic cortex and was also necessary for proper spindle orientation.
We propose that Dlg1 acts primarily to recruit LGN to the cortex and that Dlg1 localization may additionally provide instructive cues for spindle orientation.
http://jcb.rupress.org/content.....285c19d79e
What drugs are you on Dio?
I want some of that.
Topoisomerase II has to work late
Chromatid-untangling enzyme takes longer than expected to complete job.
Without the enzyme topoisomerase II (topo II), sister chromatids can’t separate during mitosis.
Contrary to conventional wisdom, however, the enzyme is still unraveling tangled DNA molecules during anaphase in budding yeast.
Animal chromosomes are typically longer than their yeast counterparts, though, and the impact of length on sister chromatid intertwines (SCI) resolution is unclear.
doi: 10.1083/jcb.2066if
http://jcb.rupress.org/content.....285c19d79e
#451 AVS
Here it is:
Go for it! Enjoy it too! It’s for everyone who wants it!
And it’s free! Someone paid it all, so you and I don’t have to pay it. Isn’t that great? 🙂
Don’t wait longer… go for it, now!
🙂
AVS, so your response to all of Dionisio’s hard work in documenting the astonishing complexity in the cell, complexity that far exceeds man’s ability to imitate, is to ask if he is on drugs???
But AVS, would it not be far more reasonable to suppose that the person who said such unfathomed complexity arose by accidental processes (as you do), instead of by purposeful intent, was the one on drugs?
Dio has been copying and pasting the summaries of random scientific papers here for four months now. Not holding a conversation with anyone or anything of the sort, just mindlessly copying and pasting.
I wish I had that much time on my hands, and was entertained by such simplicity.
AVS, So your response is to ignore my question to you? Let me ask again,, Is the reason that you believe accidental processes can produces complexity that far exceeds man’s ability to imitate because you on drugs?
Admitting you have a problem is the first step in recovery AVS!
Well first of all it’s a loaded question, BA. You are assuming to know what I do and do not believe in, something mr. news just did in another post. Also, how can we imitate something we don’t fully understand? Of course we’re going to have trouble doing this.
The question was obviously meant to be funny/ridiculous and the fact that you are pushing me to answer it still shows how little respect you give and therefore how little respect you deserve. I shouldn’t even be responding to you, you’re not worth the effort.
So you refuse to honestly answer the question as to if you are on drugs? Now I’m really starting to get suspicious!
#454 bornagain77
Exactly! 🙂
I could not have said it better. Thank you.
BTW, I’m surprised that the ‘drug’ reference came from no other than the same person who posted the below comments in this old thread:
http://www.uncommondescent.com.....ical-form/
49 AVS March 31, 2014 at 9:06 pm
50 AVS March 31, 2014 at 9:18 pm
56 AVS March 31, 2014 at 9:52 pm
72. AVS March 31, 2014 at 10:53 pm
#454 bornagain77
You asked:
Here’s what AVS wrote on March 31, 2014:
Would that comment give us an idea about a possible answer to your question? 🙂
Facing a strong challenge to their weak belief?
The journal Biosemiotics provides a platform for exceptional peer-reviewed papers that is as broad as the rapidly growing discipline for which it is named.
Its coverage spans a range of disciplines, bridging biology, philosophy, linguistics and the communication sciences.
Conceived in the insight that the genetic code is a language as old as life itself, and grounded in the study of signs, of communication and of information in organisms, biosemiotics is evolving today toward the challenge of naturalizing not only biological information but also biological meaning, in the belief that signs and codes are fundamental components of the living world.[???]
Biosemiotics offers an advanced forum for the exchange of ideas on this exciting new area of biological theory.
It serves a readership comprising biosemioticians themselves, along with interested researchers in disciplines from social semiotics to community ecology, from communication science to artificial intelligence.
http://link.springer.com/journal/12304
Here are the articles posted in this journal:
http://link.springer.com/searc.....l-id=12304
Definitely they have a very difficult task ahead. Perhaps it might be interesting to watch how they handle it and what arguments they present to support their beliefs.
Chromosome length and perinuclear attachment constrain resolution of DNA intertwines
doi: 10.1083/jcb.201404039
To allow chromosome segregation, topoisomerase II (topo II) must resolve sister chromatid intertwines (SCI) formed during deoxynucleic acid (DNA) replication.
How this process extends to the full genome is not well understood.
In budding yeast, the unique structure of the ribosomal DNA (rDNA) array is thought to cause late SCI resolution of this genomic region during anaphase.
In this paper, we show that chromosome length, and not the presence of rDNA repeats, is the critical feature determining the time of topo II–dependent segregation.
Segregation of chromosomes lacking rDNA also requires the function of topo II in anaphase, and increasing chromosome length aggravates missegregation in topo II mutant cells.
Furthermore, anaphase Stu2-dependent microtubule dynamics are critical for separation of long chromosomes.
Finally, defects caused by topo II or Stu2 impairment depend on attachment of telomeres to the nuclear envelope.
We propose that topological constraints imposed by chromosome length and perinuclear attachment determine the amount of SCI that topo II and dynamic microtubules resolve during anaphase.
http://jcb.rupress.org/content/206/6/719
Clarification:
In the many research examples we see in this thread, one can note elaborate cellular and molecular choreographies associated with what KF calls FSCO/I and GP refers to as dFCSI.
As one could note in most of these posts, serious scientists are very busy trying to figure out how those complex processes work.
They don’t have time to think about how they appeared to begin with. IOW, OOL discussions are irrelevant to resolve their research issues at this point.
Every new discovery reveals more FSCO/I and dFCSI that demand explanation.
Any question about how an intelligent agent does his work seems kind of premature, in light of our lack of detailed information about the actual functioning of the observed processes.
One might have to wait quite a while for an answer to such a question. First things first.
#463 addendum
Important clarification by KF in another thread:
Here’s the link to the above quoted KF’s post:
Mechanisms regulating stem cell polarity and the specification of asymmetric divisiones
The ability of cells to divide asymmetrically to produce two different cell types provides the cellular diversity found in every multicellular organism.
Asymmetric localization of cell-cell junctions and/or intrinsic cell fate determinants and position within specific environment (“niche”) are examples of mechanisms used to specify cell polarity and direct asymmetric divisions.
During development, asymmetric divisions provide the basis for establishment of the body axis and cell fate determination in a range of processes.
Subsequently, asymmetric cell divisions play a critical role in maintaining adult stem cell populations, while at the same time generating an adequate number of differentiating daughter cells to maintain tissue homeostasis and repair.
Loss of cell polarity, and consequently the potential for asymmetric divisions, is often linked to excessive stem cell self-renewal and tumorigenesis.
Here we will discuss multiple factors and mechanisms that imbue cells with polarity to facilitate an asymmetric outcome to stem cell divisions, assuring self-renewal and maintenance of the stem cell pool.
Asymmetric division is a property of stem cells that leads to the generation of two cells that can adopt different fates.
One has the potential to renew stem cell identity and continue to divide in an asymmetric manner, whereas the other cell will differentiate along a specific lineage.
In some cases, factors within the dividing mother cell lead to the differential segregation of cell fate determinants to give two distinct daughters upon division.[intrinsic asymmetry]
In others, however, establishment of different fates is reinforced through signaling from neighboring cells. [extrinsic asymmetry]
Ultimately, asymmetric divisions are regulated directly by genes that control the process of asymmetric cell division itself or determine the distinct cell fates of the two daughter cells.
http://www.stembook.org/node/562
Biased segregation of DNA and centrosomes — moving together or drifting apart?
doi:10.1038/nrm2784
Old and newly synthesized centrosomes have different microtubule nucleating abilities and they contribute to cell polarity when they migrate to opposite poles during cell division.
The asymmetric localization of epigenetic marks and kinetochore proteins could lead to the differential recognition of sister chromatids and the biased segregation of DNA strands to daughter cells during cell division.
We propose that this asymmetric localization is linked to biased chromatid segregation, which might also be related to the acquisition of distinct cell fates after mitosis.
http://www.nature.com/nrm/jour.....m2784.html
DNA asymmetry and cell fate regulation in stem cells
DOI: 10.1016/j.semcdb.2013.05.008
Highlights
•
Cell divisions can be invariant, or stochastic where they can potentially alternate between symmetric and asymmetric divisions.
•
We propose that all cell divisions are de facto asymmetric in nature, and that symmetric divisions do not seize this opportunity to generate distinct cell fates.
•
Segregation of chromatids containing oldest DNA strands to only one daughter cell has been linked to cell fate choice.
•
The coupling of transcription and pre- or post-replication events in S-phase could mark chromatids for future selection and asymmetric segregation during mitosis.
Abstract
The semi-conservative nature of DNA replication has suggested that identical DNA molecules within chromatids are inherited by daughter cells after cell division.
Numerous reports of non-random DNA segregation in prokaryotes and eukaryotes suggest that this is not always the case, and that epigenetic marks on chromatids, if not the individual DNA strands themselves, could have distinct signatures.
Their selective distribution to daughter cells provides a novel mechanism for gene and cell fate regulation by segregating chromatids asymmetrically.
Here we highlight some examples and potential mechanisms that can regulate this process.
We propose that cellular asymmetry is inherently present during each cell division, and that it provides an opportunity during each cell cycle for moderating cell fates.
http://www.sciencedirect.com/s.....2113000748
Numb is Required for the Production of Terminal Asymmetric Cell Divisions in the Developing Retina
doi: 10.1523/JNEUROSCI.4127-12.2012
In the developing nervous system, cell diversification depends on the ability of neural progenitor cells to divide asymmetrically to generate daughter cells that acquire different identities.
While much work has recently focused on the mechanisms controlling self-renewing asymmetric divisions producing a differentiating daughter and a progenitor, little is known about mechanisms regulating how distinct differentiating cell types are produced at terminal divisions.
Here we study the role of the endocytic adaptor protein Numb in the developing mouse retina.
Using clonal numb inactivation in retinal progenitor cells (RPCs), we show that Numb is required for normal cell-cycle progression at early stages, but is dispensable for the production of self-renewing asymmetric cell divisions.
At late stages, however, Numb is no longer required for cell-cycle progression, but is critical for the production of terminal asymmetric cell divisions.
In the absence of Numb, asymmetric terminal divisions that generate a photoreceptor and a non-photoreceptor cell are decreased in favor of symmetric terminal divisions generating two photoreceptors.
Using live imaging in retinal explants, we show that a Numb fusion protein is asymmetrically inherited by the daughter cells of some late RPC divisions.
Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions.
http://www.jneurosci.org/conte.....7.abstract
Numb Expression and Asymmetric versus Symmetric Cell Division in Distal Embryonic Lung Epithelium
doi: 10.1369/0022155412451582
Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration.
Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration.
The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate.
Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development.
Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells.
Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2.
Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells.
These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area.
http://jhc.sagepub.com/content/60/9/675.abstract
Evidence for close side-chain packing in an early protein folding intermediate previously assumed to be a molten globule
doi: 10.1073/pnas.1410630111
Significance
Molten globules—defined as compact protein conformations with significant secondary structure but only loosely packed tertiary structure—have been hypothesized to be general folding intermediates.
In this work we investigate one folding intermediate long thought to be a molten globule and find significant evidence that it likely has a well-folded region, with closely packed tertiary structure.
These results suggest that the evidence for moltenness in other protein folding intermediates should be revisited and that even for fairly simple, small proteins, exclusion of water can occur before the rate-limiting step to folding.
The molten globule, a conformational ensemble with significant secondary structure but only loosely packed tertiary structure, has been suggested to be a ubiquitous intermediate in protein folding.
However, it is difficult to assess the tertiary packing of transiently populated species to evaluate this hypothesis.
Escherichia coli RNase H is known to populate an intermediate before the rate-limiting barrier to folding that has long been thought to be a molten globule.
We investigated this hypothesis by making mimics of the intermediate that are the ground-state conformation at equilibrium, using two approaches: a truncation to generate a fragment mimic of the intermediate, and selective destabilization of the native state using point mutations.
Spectroscopic characterization and the response of the mimics to further mutation are consistent with studies on the transient kinetic intermediate, indicating that they model the early intermediate.
Both mimics fold cooperatively and exhibit NMR spectra indicative of a closely packed conformation, in contrast to the hypothesis of molten tertiary packing.
This result is important for understanding the nature of the subsequent rate-limiting barrier to folding and has implications for the assumption that many other proteins populate molten globule folding intermediates.
http://www.pnas.org/content/ea......html?etoc
Effects of geometry and chemistry on hydrophobic salvation [time to remodel?]
doi: 10.1073/pnas.1406080111
Significance
The solvation free energy of a molecule includes the free energy required to remove solvent from what will become the molecular interior and the free energy gained from dispersive interactions between the solute and solvent.
Traditionally, these free energies have been assumed to be proportional to the surface area of the molecule.
However, we computed these free energies for a series of alkanes and four configurations of decaalanine and showed that although these free energies were linear in the surface area for each set of molecules, each atom’s contributions to these energies depended on correlations with its surrounding atoms.
The atomic contributions to these energies were therefore not additive.
This finding suggests that most current hydrophobic models are unsatisfactory. [oops!]
Abstract
Inserting an uncharged van der Waals (vdw) cavity into water disrupts the distribution of water and creates attractive dispersion interactions between the solvent and solute.
This free-energy change is the hydrophobic solvation energy (?Gvdw).
Frequently, it is assumed to be linear in the solvent-accessible surface area, with a positive surface tension (?) that is independent of the properties of the molecule.
However, we found that ? for a set of alkanes differed from that for four configurations of decaalanine, and ? = ?5 was negative for the decaalanines.
These findings conflict with the notion that ?Gvdw favors smaller A.
We broke ?Gvdw into the free energy required to exclude water from the vdw cavity (?Grep) and the free energy of forming the attractive interactions between the solute and solvent (?Gatt) and found that ? ?rep and ?att < 0.
Additionally, ?att and ?rep for the alkanes differed from those for the decaalanines, implying that none of ?Gatt, ?Grep, and ?Gvdw can be computed with a constant surface tension.
We also showed that ?Gatt could not be computed from either the initial or final water distributions, implying that this quantity is more difficult to compute than is sometimes assumed.
Finally, we showed that each atom’s contribution to ?rep depended on multibody interactions with its surrounding atoms, implying that these contributions are not additive.
These findings call into question some hydrophobic models.
http://www.pnas.org/content/ea......html?etoc
#471 misspelling error correction
The word ‘solvation‘ in the title of the post #471 was misspelled by the autocorrect feature of the word processing software.
BTW, I’m not aware of that concept ‘hydrophobic salvation’ but I’m aware of the most important ‘salvation’ by faith alone. 🙂
Any news from The Third Way front yet? Any progress there? 😉
Addendum to posts #463 and #464
As science gets deeper into the nature of Nature, the revealed elaborate complexity is a more convincing evidence that leads to…
generation of a remarkable diversity of cell types from a surprisingly small set of precursor cells?
Surprisingly? Why surprised? What else did they expect? 🙂
Control of neural stem cell self-renewal and differentiation in drosophila.
The neural stem cells called neuroblasts, have the ability to self-renew and at the same time produce many different types of neurons and glial cells.
In the central brain and ventral ganglia, neuroblasts are specified and delaminate from the neuroectoderm during embryonic development under the control of proneural and neurogenic genes.
In contrast, in the optic lobes, neuroepithelial cells are transformed into neuroblasts postembryonically by a spatial wave of proneural gene expression.
Central brain and ventral nerve cord neuroblasts manifest a short embryonic proliferation period followed by a stage of quiescence and then undergo a prolonged postembryonic proliferation period during which most of the differentiated neurons of the adult CNS are generated.
While most neuroblasts belong to a type I class that produces neuronal lineages through non-self-renewing ganglion mother cells, a small subset of type II neuroblasts generates exceptionally large neuronal lineages through self-renewing intermediate progenitor cells that have a transit amplifying function.
All neuroblasts in the CNS generate their neural progeny through an asymmetric cell division mode in which the interplay of apical complex and basal complex molecules in the mitotically active progenitor results in the segregation of cell fate determinants into the smaller more differentiated daughter cell.
Defects in this molecular control of asymmetric cell division in neuroblasts can result in brain tumor formation.
Proliferating neuroblast lineages in the developing CNS utilize transcription factor cascades as a generic mechanism for temporal patterning and birth order-dependent determination of differential neural cell fate.
This contributes to the generation of a remarkable diversity of cell types in the developing CNS from a surprisingly small set of neural stem cell-like precursors.
http://www.ncbi.nlm.nih.gov/pubmed/24902665
BA77
RE: your questions posted on #454, #456 and #458.
Any hope you’ll get a reply from our interlocutor?
🙂
Well Dionisio, my experience with people who prefer to live in a fantasy land, i.e. drug addicts and alcoholics, is that they will either ignore you or lash out at the people who even mention that they may have a problem. Fortunately, reality itself has a way of intruding on their dream world and waking them from their denialism.
BA77, I see what you mean. Thank you.
I pray that the interlocutor gets pulled out from that fantasyland daydreaming addiction before it’s too late.
Anyway, they ain’t seen nothing yet. The best part (for us) in this debate is still ahead. Let’s just wait and see. 🙂
There yet? nope, but close… 🙂
How the circadian clock regulates the timing of sleep is poorly understood.
The protein machinery that regulates asymmetric cell division (ACD) has been identified in Drosophila, but how this machinery acts to allow the establishment of differential cell fates is not entirely understood.
Over the past years, a conserved protein machinery for ACD has been identified, but how this machinery connects to the organism architecture is less clear.
The process of ACD involves the establishment of a polarity axis, the orientation of the mitotic spindle, the polarized distribution of cell fate determinants, and, ultimately, the establishment of different daughter cell fates.
Further experiments will be needed to address these issues and clarify the instructive role of Bnd in establishing cell asymmetry …
Why Bnd is also found at centrosomes and at the spindle is harder to explain.
these studies may therefore be relevant for a variety of biological processes in higher organisms as well
The molecular pathways by which the circadian clock modulates the timing of sleep are unknown.
http://www.sdbonline.org/sites.....eruola.htm
Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis
The preimplantation period of early embryonic development is devoted to the specification of two extraembryonic tissues and their spatial segregation from the pluripotent epiblast.
During this period two cell fate decisions are made while cells gradually lose their totipotency.
The first fate decision involves the segregation of the extraembryonic trophectoderm (TE) lineage from the inner cell mass (ICM); the second occurs within the ICM and involves the segregation of the extraembryonic primitive endoderm (PrE) lineage from the pluripotent epiblast (EPI) lineage, which eventually gives rise to the embryo proper.
Multiple determinants, such as differential cellular properties, signaling cues and the activity of transcriptional regulators, influence lineage choice in the early embryo.
Here, we provide an overview of our current understanding of the mechanisms governing these cell fate decisions ensuring proper lineage allocation and segregation, while at the same time providing the embryo with an inherent flexibility to adjust when perturbed.
doi: 10.1002/dvg.22368
http://www.ncbi.nlm.nih.gov/pubmed/23349011
Formation of a polarised primitive endoderm layer in embryoid bodies requires fgfr/erk signalling.
The primitive endoderm arises from the inner cell mass during mammalian pre-implantation development.
It faces the blastocoel cavity and later gives rise to the extraembryonic parietal and visceral endoderm.
Here, we investigate a key step in primitive endoderm development, the acquisition of apico-basolateral polarity and epithelial characteristics by the non-epithelial inner cell mass cells.
Embryoid bodies, formed from mouse embryonic stem cells, were used as a model to study this transition.
The outer cells of these embryoid bodies were found to gradually acquire the hallmarks of polarised epithelial cells and express markers of primitive endoderm cell fate.
Fgf receptor/Erk signalling is known to be required for specification of the primitive endoderm, but its role in polarisation of this tissue is less well understood.
To investigate the function of this pathway in the primitive endoderm, embryoid bodies were cultured in the presence of a small molecule inhibitor of Mek.
This inhibitor caused a loss of expression of markers of primitive endoderm cell fate and maintenance of the pluripotency marker Nanog.
In addition, a mislocalisation of apico-basolateral markers and disruption of the epithelial barrier, which normally blocks free diffusion across the epithelial cell layer, occurred.
Two inhibitors of the Fgf receptor elicited similar phenotypes, suggesting that Fgf receptor signalling promotes Erk-mediated polarisation.
This data shows that primitive endoderm cells of the outer layer of embryoid bodies gradually polarise, and formation of a polarised primitive endoderm layer requires the Fgf receptor/Erk signalling pathway.
doi: 10.1371/journal.pone.0095434. eCollection 2014
http://www.ncbi.nlm.nih.gov/pubmed/24752320
Challenging bioinformatics, imaging, computational biology issues
http://www.ncbi.nlm.nih.gov/pubmed/24672759
close look at the mammalian blastocyst: epiblast and primitive endoderm formation.
During early development, the mammalian embryo undergoes a series of profound changes that lead to the formation of two extraembryonic tissues–the trophectoderm and the primitive endoderm.
These tissues encapsulate the pluripotent epiblast at the time of implantation.
The current model proposes that the formation of these lineages results from two consecutive binary cell fate decisions.
The first controls the formation of the trophectoderm and the inner cell mass, and the second controls the formation of the primitive endoderm and the epiblast within the inner cell mass.
While early mammalian embryos develop with extensive plasticity, the embryonic pattern prior to implantation is remarkably reproducible.
Here, we review the molecular mechanisms driving the cell fate decision between primitive endoderm and epiblast in the mouse embryo and integrate data from recent studies into the current model of the molecular network regulating the segregation between these lineages and their subsequent differentiation.
doi: 10.1007/s00018-014-1630-3. Epub 2014 May 4.
http://www.ncbi.nlm.nih.gov/pubmed/24794628
The Oct4 protein: more than a magic stemness marker
The Oct4 protein, encoded by the Pou5f1 gene was the very first master gene, discovered 25 years ago, to be absolutely required for the stemness properties of murine and primate embryonic stem cells.
This transcription factor, which has also been shown to be essential for somatic cell reprogrammation, displays various functions depending upon its level of expression and has been quoted as a “rheostat” gene.
Oct4 protein is in complexes with many different partners and its activity depends upon fine post-translational modifications.
This review aims at revisiting some properties of this protein, which has not yet delivered all its potentialities.
http://www.ncbi.nlm.nih.gov/pubmed/25232507
A series of fortuitous genetic events?
If I had this creative imagination I could easily become a famous bestselling author in the fiction genre:
http://www.the-scientist.com//.....onnection/
Regulatory Principles of Pluripotency: From the Ground State Up
DOI: http://dx.doi.org/10.1016/j.stem.2014.09.015
Pluripotency is the remarkable capacity of a single cell to engender all the specialized cell types of an adult organism.
This property can be captured indefinitely through derivation of self-renewing embryonic stem cells (ESCs), which represent an invaluable platform to investigate cell fate decisions and disease.
Recent advances have revealed that manipulation of distinct signaling cues can render ESCs in a uniform “ground state” of pluripotency, which more closely recapitulates the pluripotent naive epiblast.
Here we discuss the extrinsic and intrinsic regulatory principles that underpin the nature of pluripotency and consider the emerging spectrum of pluripotent states.
http://www.cell.com/cell-stem-.....ll%20Press
Cell-to-cell expression variability + signal reinforcement lead to early lineage segregation.
doi: 10.1038/ncb2881.
It is now recognized that extensive expression heterogeneities among cells precede the emergence of lineages in the early mammalian embryo.
To establish a map of pluripoten epiblast (EPI) versus primitive endoderm (PrE) lineage segregation within the inner cell mass (ICM) of the mouse blastocyst, we characterized the gene expression profiles of individual ICM cells.
Clustering analysis of the transcriptomes of 66 cells demonstrated that initially they are non-distinguishable.
Early in the segregation, lineage-specific marker expression exhibited no apparent correlation, and a hierarchical relationship was established only in the late blastocyst.
Fgf4 exhibited a bimodal expression at the earliest stage analysed, and in its absence, the differentiation of PrE and EPI was halted, indicating that Fgf4 drives, and is required for, ICM lineage segregation.
These data lead us to propose a model where stochastic cell-to-cell expression heterogeneity followed by signal reinforcement underlies ICM lineage segregation by antagonistically separating equivalent cells.
http://www.ncbi.nlm.nih.gov/pubmed/24292013
Epigenetic memory: the Lamarckian brain
Andre Fischer
DOI 10.1002/embj.201387637 | Published online 09.04.2014
The EMBO Journal (2014) embj.201387637
Memory formation via gene expression control
Is the bold word politically correct?
Functional roles of nucleosome stability and dynamics
doi: 10.1093/bfgp/elu038
Nucleosome is a histone–DNA complex known as the fundamental repeating unit of chromatin.
Up to 90% of eukaryotic DNA is wrapped around consecutive octamers made of the core histones H2A, H2B, H3 and H4.
Nucleosome positioning affects numerous cellular processes that require robust and timely access to genomic DNA, which is packaged into the tight confines of the cell nucleus.
In living cells, nucleosome positions are determined by intrinsic histone–DNA sequence preferences, competition between histones and other DNA-binding proteins for genomic sequence, and ATP-dependent chromatin remodelers.
We discuss the major energetic contributions to nucleosome formation and remodeling, focusing especially on partial DNA unwrapping off the histone octamer surface.
DNA unwrapping enables efficient access to nucleosome-buried binding sites and mediates rapid nucleosome removal through concerted action of two or more DNA-binding factors.
High-resolution, genome-scale maps of distances between neighboring nucleosomes have shown that DNA unwrapping and nucleosome crowding (mutual invasion of nucleosome territories) are much more common than previously thought.
Ultimately, constraints imposed by nucleosome energetics on the rates of ATP-dependent and spontaneous chromatin remodeling determine nucleosome occupancy genome-wide, and shape pathways of cellular response to environmental stresses.
http://bfg.oxfordjournals.org/.....581de47e66
488 addendum
Here’s the link to the referred article:
http://emboj.embopress.org/con......201387637
490 addendum
Here’s some information about the scientist who apparently wrote the original article containing the controversial term:
http://www.dzne.de/en/sites/go.....scher.html
488 addendum 2
Here’s a separate source to the same article where the controversial term is used:
http://onlinelibrary.wiley.com.....87637/full
Event timing at the single-cell level
doi: 10.1093/bfgp/els057
The timing of a cellular event often hides critical information on the process leading to the event.
Our ability to measure event times in single cells along with other quantities allow us to learn about the drivers of the timed process and its downstream effects.
In this review, we cover different types of events that have been timed in single cells, methods to time such events and types of analysis that have been applied to event timings.
We show how different timing distributions suggest different natures for the process. The statistical relations between the timing of different events may reveal how their respective processes are related biologically: Do they occur in sequence or in parallel? Are they independent or inter-dependent?
Finally, quantifying morphological and molecular variables may help assess their contribution to the timing of an event and its related process.
http://bfg.oxfordjournals.org/.....7b980de051
The vertebrate corneal epithelium: From early specification to constant renewal
DOI: 10.1002/dvdy.24179
The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function.
Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult.
Recent progress in the molecular and stem cell biology of corneal morphogenesis and renewal shows that it can serves as a paradigm for epithelial /mesenchymal organ biology.
This review will synthesize historical knowledge together with recent data to present a consistent overview of cornea specification, formation, maturation, and maintenance.
This should be of interest not only to developmental biologists but also ophthalmologists, as several human vision problems are known to be rooted in defects in corneal development.
Developmental Dynamics 243:1226–1241, 2014. © 2014 Wiley Periodicals, Inc.
http://onlinelibrary.wiley.com.....9/abstract
Protein dynamics during presynaptic-complex assembly on individual single-stranded DNA molecules
doi:10.1038/nsmb.2886
Homologous recombination is a conserved pathway for repairing double-stranded breaks, which are processed to yield single-stranded DNA overhangs that serve as platforms for presynaptic-complex assembly.
Here we use single-molecule imaging to reveal the interplay between Saccharomyces cerevisiae RPA, ?Rad52 and ?Rad51 during presynaptic-complex assembly.
We show that ?Rad52 binds RPA–ssDNA and suppresses RPA turnover, highlighting an unanticipated regulatory influence on protein dynamics. ?
Rad51 binding extends the ssDNA, and ?Rad52–RPA clusters remain interspersed along the presynaptic complex.
These clusters promote additional binding of RPA and ?Rad52.
Our work illustrates the spatial and temporal progression of the association of RPA and ?Rad52 with the presynaptic complex and reveals a new RPA–?Rad52–?Rad51–ssDNA intermediate, with implications for how the activities of ?Rad52 and RPA are coordinated with ?Rad51 during the later stages of recombination.
http://www.nature.com/nsmb/jou......2886.html
http://www.nature.com/nsmb/jou......2886.html
Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems
doi:10.1038/nsmb.2876
Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization.
Why are certain mRNA transported to a distal location and translated on-site?
Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells.
Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity.
Proteins synthesized at distal locations frequently contain intrinsically disordered segments.
These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications.
Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors.
Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies.
Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation.
http://www.nature.com/nsmb/jou......2876.html
Specification of sensory neurons occurs through diverse developmental programs functioning in the brain and spinal cord
DOI: 10.1002/dvdy.24184
Vertebrates possess two populations of sensory neurons located within the central nervous system (CNS): Rohon-Beard (RB) and mesencephalic trigeminal nucleus (MTN) neurons.
RB neurons are transient spinal cord neurons whilst MTN neurons are the proprioceptive cells that innervate the jaw muscles.
It has been suggested that MTN and RB neurons share similarities and may have a common developmental program, but it is unclear how similar or different their development is.
We have dissected RB and MTN neuronal specification in zebrafish.
We find that RB and MTN neurons express a core set of genes indicative of sensory neurons, but find these are also expressed by adjacent diencephalic neurons.
Unlike RB neurons, our evidence argues against a role for the neural crest during MTN development.
We additionally find that neurogenin1 function is dispensable for MTN differentiation, unlike RB cells and all other sensory neurons.
Finally, we demonstrate that, although Notch signalling is involved in RB development, it is not involved in the generation of MTN cells.
Our work reveals fundamental differences between the development of MTN and RB neurons and suggests that these populations are non-homologous and thus have distinct developmental and, probably, evolutionary origins.
Developmental Dynamics, 2014. © 2014 Wiley Periodicals, Inc.
http://onlinelibrary.wiley.com.....4/abstract
A perspective on proteomics in cell biology
DOI: http://dx.doi.org/10.1016/j.tcb.2013.10.010
Proteomic strategies facilitate system-wide analyses of protein complexes.
•Isotope labelling allows quantitative measurement of protein properties, not only their identification.
•There is a major need to organise effective community sharing of the proteomic data mountain.
•The integration of proteomic data with other online data repositories must be improved.
During the past 15 years mass spectrometry (MS)-based analyses have become established as the method of choice for direct protein identification and measurement.
Owing to the remarkable improvements in the sensitivity and resolution of MS instruments, this technology has revolutionised the opportunities available for the system-wide characterisation of proteins, with wide applications across virtually the whole of cell biology.
In this article we provide a perspective on the current state of the art and discuss how the future of cell biology research may benefit from further developments and applications in the field of MS and proteomics, highlighting the major challenges ahead for the community in organising the effective sharing and integration of the resulting data mountain.
http://www.cell.com/trends/cel.....13)00191-8
Lysosome: regulator of lipid degradation pathways
DOI: http://dx.doi.org/10.1016/j.tcb.2014.06.006
•Lipophagy is a transcriptionally regulated process.
•The lysosome as a sensor of lipophagy induction.
•Nuclear receptors link lipophagy to lipid catabolism.
Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation.
Recent studies have revealed that the lysosomal–autophagic pathway plays an important part in the early steps of lipid degradation.
In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family.
In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting.
http://www.cell.com/trends/cel.....14)00103-2
Sister kinetochores are mechanically fused during meiosis
DOI: 10.1126/science.1256729
Production of healthy gametes requires a reductional meiosis I division in which replicated sister chromatids comigrate, rather than separate as in mitosis or meiosis II.
Fusion of sister kinetochores during meiosis I may underlie sister chromatid comigration in diverse organisms, but direct evidence for such fusion has been lacking.
We used laser trapping and quantitative fluorescence microscopy to study native kinetochore particles isolated from yeast.
Meiosis I kinetochores formed stronger attachments and carried more microtubule-binding elements than kinetochores isolated from cells in mitosis or meiosis II.
The meiosis I–specific monopolin complex was both necessary and sufficient to drive these modifications.
Thus, kinetochore fusion directs sister chromatid comigration, a conserved feature of meiosis that is fundamental to Mendelian inheritance.
http://www.sciencemag.org/cont.....8.abstract
chromosome attachments
http://www.fredhutch.org/en/ne.....ments.html
How mitosis keeps itself in order
Researchers describe how multiple mechanisms ensure that mitotic proteins are degraded in the correct sequence.
doi: 10.1083/jcb.2071if
Cells progress through mitosis by switching protein activities on and off in a clearly defined order.
The ubiquitin ligase APC/C deactivates mitotic proteins by targeting them for degradation by the proteasome.
The APC/C is activated by two different subunits that recognize short sequence motifs, known as D and KEN boxes, in the target proteins.
In early mitosis, once the spindle assembly checkpoint (SAC) has been satisfied, the APC/C partners with the activating subunit Cdc20 to promote the cell’s entry into anaphase.
The APC/C then pairs up with Cdh1 to degrade a different set of substrates and promote the cell’s exit from mitosis.
CBut even substrates targeted by the same activating subunit are degraded in a specific sequence
http://jcb.rupress.org/content.....jcb.2071if
Cell polarization in early embryos
doi: 10.1083/jcb.201407064
Polarization of early embryos along cell contact patterns—referred to in this paper as radial polarization—provides a foundation for the initial cell fate decisions and morphogenetic movements of embryogenesis.
Although polarity can be established through distinct upstream mechanisms in Caenorhabditis elegans, Xenopus laevis, and mouse embryos, in each species, it results in the restriction of PAR polarity proteins to contact-free surfaces of blastomeres.
In turn, PAR proteins influence cell fates by affecting signaling pathways, such as Hippo and Wnt, and regulate morphogenetic movements by directing cytoskeletal asymmetries.
http://jcb.rupress.org/content/206/7/823.abstract
Signalling dynamics in the spindle checkpoint response
doi:10.1038/nrm3888
The spindle checkpoint ensures proper chromosome segregation during cell division.
Unravelling checkpoint signalling has been a long-standing challenge owing to the complexity of the structures and forces that regulate chromosome segregation.
New reports have now substantially advanced our understanding of checkpoint signalling mechanisms at the kinetochore, the structure that connects microtubules and chromatin.
In contrast to the traditional view of a binary checkpoint response — either completely on or off — new findings indicate that the checkpoint response strength is variable.
This revised perspective provides insight into how checkpoint bypass can lead to aneuploidy and informs strategies to exploit these errors for cancer treatments.
http://www.nature.com/nrm/jour.....m3888.html
The maintenance of chromosome structure: positioning and functioning of SMC complexes
doi:10.1038/nrm3857
Structural maintenance of chromosomes (SMC) complexes, which in eukaryotic cells include cohesin, condensin and the Smc5/6 complex, are central regulators of chromosome dynamics and control sister chromatid cohesion, chromosome condensation, DNA replication, DNA repair and transcription.
Even though the molecular mechanisms that lead to this large range of functions are still unclear, it has been established that the complexes execute their functions through their association with chromosomal DNA.
A large set of data also indicates that SMC complexes work as intermolecular and intramolecular linkers of DNA.
When combining these insights with results from ongoing analyses of their chromosomal binding, and how this interaction influences the structure and dynamics of chromosomes, a picture of how SMC complexes carry out their many functions starts to emerge.
http://www.nature.com/nrm/jour.....m3857.html
Bidirectional cargo transport: moving beyond tug of war
doi:10.1038/nrm3853
Vesicles, organelles and other intracellular cargo are transported by kinesin and dynein motors, which move in opposite directions along microtubules.
This bidirectional cargo movement is frequently described as a ‘tug of war’ between oppositely directed molecular motors attached to the same cargo.
However, although many experimental and modelling studies support the tug-of-war paradigm, numerous knockout and inhibition studies in various systems have found that inhibiting one motor leads to diminished motility in both directions, which is a ‘paradox of co-dependence’ that challenges the paradigm.
In an effort to resolve this paradox, three classes of bidirectional transport models — microtubule tethering, mechanical activation and steric disinhibition — are proposed, and a general mathematical modelling framework for bidirectional cargo transport is put forward to guide future experiments.
http://www.nature.com/nrm/jour.....m3853.html
Making the spindle checkpoint strong
doi:10.1038/nrm3828
Spindle checkpoint signals (generated by checkpoint proteins, including MAD1 and the RZZ (Rod–Zw10–Zwilch) complex) arrest mitosis until all kinetochores are correctly attached to spindle microtubules, whereupon checkpoint proteins are removed in a dynein-dependent manner.
http://www.nature.com/nrm/jour.....m3828.html
Polo-like kinases: structural variations lead to multiple functions
doi:10.1038/nrm3819
Members of the polo-like kinase (PLK) family are crucial regulators of cell cycle progression, centriole duplication, mitosis, cytokinesis and the DNA damage response.
PLKs undergo major changes in abundance, activity, localization and structure at different stages of the cell cycle.
They interact with other proteins in a tightly controlled spatiotemporal manner as part of a network that coordinates key cell cycle events.
Their essential roles are highlighted by the fact that alterations in PLK function are associated with cancers and other diseases.
Recent knowledge gained from PLK crystal structures, evolution and interacting molecules offers important insights into the mechanisms that underlie their regulation and activity, and suggests novel functions unrelated to cell cycle control for this family of kinases.
http://www.nature.com/nrm/jour.....m3819.html
Regulating chromosome segregation
doi:10.1038/nrm3809
Cyclin B1 and cyclin B2 have been implicated in cell cycle regulation through the activation of key regulators of early mitotic events, such as cyclin-dependent kinase 1 (CDK1).
CDK1–cyclin B1 coordinates anaphase onset by phosphorylating separase to prevent cleavage of the cohesin complex, which holds sister chromatids together until kinetochores are properly attached to spindle microtubules.
http://www.nature.com/nrm/jour.....m3809.html
Advances in whole-embryo imaging: a quantitative transition is underway
doi:10.1038/nrm3786
With the advent of imaging probes and live microscopy, developmental biologists have markedly extended our understanding of the molecular and cellular details of embryonic development.
To fully comprehend the complex mechanistic framework that forms the developing organism, quantitative studies with high fidelity in space and time are now required.
We discuss how integrating established, newly introduced and future imaging tools with quantitative analysis will ensure that imaging can fulfil its promise to elucidate how new life begins.
http://www.nature.com/nrm/jour.....m3786.html
A safety net for successful mitosis
doi:10.1038/nrm3777
The spindle assembly checkpoint (SAC) delays anaphase until all kinetochores are bound by microtubules on the mitotic spindle, to ensure accurate chromosome segregation during mitosis.
New research published in Cell now describes that cells can also transduce SAC signals during interphase to provide a secondary level of cell cycle control.
http://www.nature.com/nrm/jour.....m3777.html
Prime movers: the mechanochemistry of mitotic kinesis
doi:10.1038/nrm3768
Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation.
Kinesins are key members of these force-generating teams.
Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips.
The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation.
http://www.nature.com/nrm/jour.....m3768.html
Biology has arrived at an interesting juncture.
The last decade has seen an unprecedented explosion in the amount of information generated by the biological research community, and a concomitant rise in the challenges of sharing, archiving, integrating and analyzing it.
This is particularly acute in genomics, where next generation sequencing technologies are accelerating faster than Moore’s Law.
Serendipitously, this explosion of biological data has come at the same time that computer scientists have developed scalable data management solutions for handling the vastness of the internet; solutions including distributed file systems, cloud computing, and algorithms for efficient data-intensive computation across multiple machines.
This 2014 conference brought together biologists and computer scientists from industry and academia to discuss the challenges and trends in this quickly evolving field.
The goals included:
* Surveying data and computation challenges in the fields of genomics, medical genetics, neuroinformatics, biological imaging and agronomics.
* Identifying critical bottlenecks in distributing biological data to the community.
* Discussing solutions to growing problem of data sets that are “too big to download.”
* Debating the tension between community access to personal genomic data sets (e.g. cancer genomes) and potential impact on patient privacy.
What made this conference unique is that it examined a common problem, “How do we handle big data?” across multiple research specialties that rarely interact.
We brought together plant scientists, medical geneticists, genomicists, microscopists and neurobiologists.
The expected outcome is a greater understanding of the challenges each field faces, and the solutions that they have found.
http://www.keystonesymposia.or.....ingid=1274
Tech meets bio
doi:10.1038/nm0810-844
IBM computers and Microsoft software have been mainstays of biomedical studies for years.
But, in the past decade, software and technology companies have increasingly been taking a more active role in biological research.
http://www.nature.com/nm/journ.....0-844.html
Understanding the limits of animal models as predictors of human biology
Inferring how humans respond to external cues such as drugs, chemicals, viruses or hormones, is an essential question in biomedicine.
Very often, however, this question cannot be addressed since it is not possible to perform experiments in humans.
A reasonable alternative consists of generating responses in animal models and “translating” those results to humans.
The limitations of such translation, however, are far from clear, and systematic assessments of its actual potential are urgently needed.
sbv IMPROVER ( S: ystems B: iology V: erification for I: ndustrial M: ethodology for PRO: cess VE: rification in R: esearch) was designed as a series of challenges to address translatability between humans and rodents.
This collaborative crowd-sourcing initiative invited scientists from around the world to apply their own computational methodologies on a multi-layer systems biology dataset comprised of phosphoproteomics, transcriptomics, and cytokine data derived from normal human and rat bronchial epithelial cells exposed in parallel to 52 different stimuli under identical conditions.
Our aim was to understand the limits of species-to-species translatability at different levels of biological organization: signaling, transcriptional, and release of secreted factors (such as cytokines).
Participating teams submitted 49 different solutions across the sub-challenges; two-thirds of which were statistically significantly better than random.
Additionally, similar computational methods were found to range widely in their performance within the same challenge, and no single method emerged as a clear winner across all sub-challenges.
Finally, computational methods were able to effectively translate some specific stimuli and biological processes in the lung epithelial system, such as DNA synthesis, cytoskeleton and extracellular matrix (ECM), translation, immune/inflammation, and growth factor/proliferation pathways, better than the expected response similarity between species.
© The Author(s) 2014. Published by Oxford University Press.
#515 addendum
http://www.ncbi.nlm.nih.gov/pubmed/25236459
A crowd-sourcing approach for the construction of species-specific cell signaling networks.
Animal models are very important tools in drug discovery and for understanding human biology in general.
However many drugs that initially show promising results in rodents fail in later stages of clinical trials.
Understanding the commonalities and differences between human and rat cell signaling networks can lead to better experimental designs, improved allocation of resources and ultimately better drugs.
The sbv IMPROVER Species-Specific Network Inference challenge was designed to use the power of the crowds to build two species-specific cell signaling networks given phosphoproteomics, transcriptomics and cytokine data generated from NHBE and NRBE cells exposed to various stimuli.
A common literature-inspired reference network with 220 nodes and 501 edges was also provided as prior knowledge from which challenge participants could add or remove edges but not nodes.
Such a large network inference challenge not based on synthetic simulations but on real data presented unique difficulties in scoring and interpreting the results.
Because any prior knowledge about the networks was already provided to the participants for reference, novel ways for scoring and aggregating the results were developed.
Two human and rat consensus networks were obtained by combining all the inferred networks.
Further analysis showed that major signaling pathways were conserved between the two species with only isolated components diverging, as in the case of ribosomal S6 kinase RPS6KA1.
Overall, the consensus between inferred edges was relatively high with the.
© The Author(s) 2014. Published by Oxford University Press.
http://www.ncbi.nlm.nih.gov/pubmed/25294919
Inter-species inference of gene set enrichment in lung epithelial cells from proteomic and large transcriptomic datasets.
Translating findings in rodent models to human models has been a cornerstone of modern biology and drug development.
However, in many cases, a naive ‘extrapolation’ between the two species has not succeeded.
As a result, clinical trials of new drugs sometimes fail even after considerable success in the mouse or rat stage of development.
In addition to in vitro studies, inter-species translation requires analytical tools that can predict the enriched gene sets in human cells under various stimuli from corresponding measurements in animals.
Such tools can improve our understanding of the underlying biology and optimize the allocation of resources for drug development.
We developed an algorithm to predict differential gene set enrichment as part of the sbv IMPROVER (systems biology verification in Industrial Methodology for Process Verification in Research) Species Translation Challenge, which focused on phosphoproteomic and transcriptomic measurements of normal human bronchial epithelial (NHBE) primary cells under various stimuli and corresponding measurements in rat (NRBE) primary cells.
We find that gene sets exhibit a higher inter-species correlation compared with individual genes, and are potentially more suited for direct prediction.
Furthermore, in contrast to a similar cross-species response in protein phosphorylation states 5 and 25 min after exposure to stimuli, gene set enrichment 6 h after exposure is significantly different in NHBE cells compared with NRBE cells.
In spite of this difference, we were able to develop a robust algorithm to predict gene set activation in NHBE with high accuracy using simple analytical methods.
Implementation of all algorithms is available as source code (in Matlab) at http://bhanot.biomaps.rutgers......neSets.zip, along with the relevant data used in the analysis.
Gene sets, gene expression and protein phosphorylation data are available on request.
© The Author 2014. Published by Oxford University Press.
http://www.ncbi.nlm.nih.gov/pubmed/25152231
Molecular Modeling at the Atomic Scale: Methods and Applications in Quantitative Biology
Developments in molecular modeling from experimental and computational techniques have enabled a wide range of biological applications.
This timely summary reflects the recent advances in bridging novel algorithms and high performance computing with characterization of important biological processes, such as folding dynamics of key proteins.
It encompasses the perspectives of leading experts on this transformation in molecular biology, illustrating with state of the art examples how molecular modeling approaches are being applied to critical questions in modern quantitative biology.
http://www.crcpress.com/product/isbn/9781466562950
Metabolic requirements for the maintenance of self-renewing stem cells
doi:10.1038/nrm3772
A distinctive feature of stem cells is their capacity to self-renew to maintain pluripotency.
Studies of genetically-engineered mouse models and recent advances in metabolomic analysis, particularly in haematopoietic stem cells, have deepened our understanding of the contribution made by metabolic cues to the regulation of stem cell self-renewal.
Many types of stem cells heavily rely on anaerobic glycolysis, and stem cell function is also regulated by bioenergetic signalling, the AKT–mTOR pathway, Gln metabolism and fatty acid metabolism.
As maintenance of a stem cell pool requires a finely-tuned balance between self-renewal and differentiation, investigations into the molecular mechanisms and metabolic pathways underlying these decisions hold great therapeutic promise.
http://www.nature.com/nrm/jour.....m3772.html
8Endocycles
doi:10.1038/nrm3756
In endoreplication cell cycles, known as endocycles, cells successively replicate their genomes without segregating chromosomes during mitosis and thereby become polyploid.
Such cycles, for which there are many variants, are widespread in protozoa, plants and animals.
Endocycling cells can achieve ploidies of >200,000 C (chromatin-value); this increase in genomic DNA content allows a higher genomic output, which can facilitate the construction of very large cells or enhance macromolecular secretion.
These cells execute normal S phases, using a G1–S regulatory apparatus similar to the one used by mitotic cells, but their capability to segregate chromosomes has been suppressed, typically by downregulation of mitotic cyclin-dependent kinase activity.
The various endocycle mechanisms found in nature highlight the versatility of the cell cycle control machinery.
http://www.nature.com/nrm/jour.....m3756.html
Microtubules protect spindle assembly factors
doi:10.1038/nrm3759
The spindle assembly factors HURP (hepatoma up-regulated protein), NuSAP (nucleolar and spindle-associated protein) and TPX2 (targeting protein for XKLP2) associate with microtubules to recruit additional regulators of spindle formation, and they are degraded by APC/C (anaphase-promoting complex, also known as the cyclosome)-mediated ubiquitylation when they have fulfilled their mitotic roles.
http://www.nature.com/nrm/jour.....m3759.html
Centrosomes
A new partner for BRCA1–BARD1
doi:10.1038/nrm3733
In addition to being a key factor for DNA repair, the BRCA1 (breast cancer 1)–BARD1 (BRCA1-associated RING domain 1) heterodimer affects other cellular processes, including centrosome regulation.
http://www.nature.com/nrm/jour.....m3733.html
Atmin mediates kidney morphogenesis by modulating Wnt signaling
doi: 10.1093/hmg/ddu246
The DNA damage protein and transcription factor Atmin (Asciz) is required for both lung tubulogenesis and ciliogenesis.
Like the lungs, kidneys contain a tubular network that is critical for their function and in addition, renal ciliary dysfunction has been implicated in the pathogenesis of cystic kidney disease.
Using the Atmin mouse mutant Gasping6 (Gpg6), we investigated kidney development and found it severely disrupted with reduced branching morphogenesis, resulting in fewer epithelial structures being formed.
Unexpectedly, transcriptional levels of key cilia associated genes were not altered in AtminGpg6/Gpg6 kidneys.
Instead, Gpg6 homozygous kidneys exhibited altered cytoskeletal organization and modulation of Wnt signaling pathway molecules, including ?-catenin and non-canonical Wnt/planar cell polarity (PCP) pathway factors, such as Daam2 and Vangl2.
Wnt signaling is important for kidney development and perturbation of Wnt signaling pathways can result in cystic, and other, renal abnormalities.
In common with other PCP pathway mutants, AtminGpg6/Gpg6 mice displayed a shortened rostral-caudal axis and mis-oriented cell division.
Moreover, intercrosses between AtminGpg6/+ and Vangl2Lp/+ mice revealed a genetic interaction between Atmin and Vangl2.
Thus we show for the first time that Atmin is critical for normal kidney development and we present evidence that mechanistically, Atmin modifies Wnt signaling pathways, specifically placing it as a novel effector molecule in the non-canonical Wnt/PCP pathway.
The identification of a novel modulator of Wnt signaling has important implications for understanding the pathobiology of renal disease.
http://hmg.oxfordjournals.org/.....c0b2f241c9
epigenetic mediator expression and function in embryonic blastomeres
doi: 10.1093/hmg/ddu212
A map of human embryo development that combines imaging, molecular, genetic and epigenetic data for comparisons to other species and across pathologies would be greatly beneficial for basic science and clinical applications.
Here, we compared mRNA and protein expression of key mediators of DNA methylation and histone modifications between mouse and human embryos, embryos from fertile/infertile couples, and following growth factor supplementation.
We observed that individual mouse and human embryos are characterized by similarities and distinct differences in DNA methylation and histone modification patterns especially at the single-cell level.
In particular, while mouse embryos first exhibited sub-compartmentalization of different histone modifications between blastomeres at the morula stage and cell sub-populations in blastocysts, differential histone modification expression was detected between blastomeres earlier in human embryos at the four- to eight-cell stage.
Likewise, differences in epigenetic mediator expression were also observed between embryos from fertile and infertile couples, which were largely equalized in response to growth factor supplementation, suggesting that select growth factors might prevent alterations in epigenetic profiles during prolonged embryo culture.
Finally, we determined that reduced expression via morpholino technologies of a single histone-modifying enzyme, Rps6ka4/Msk2, resulted in cleavage-stage arrest as assessed by time-lapse imaging and was associated with aneuploidy generation.
Taken together, data document differences in epigenetic patterns between species with implications for fertility and suggest functional roles for individual epigenetic factors during pre-implantation development.
http://hmg.oxfordjournals.org/.....6ef6ee92ef
epigenome reorganization during oocyte differentiation and early embryogenesis
doi: 10.1093/bfgp/elu007
In sexually reproducing organisms, propagation of the species relies on specialized haploid cells (gametes) produced by germ cells.
During their development in the adult germline, the female and male gametes undergo a complex differentiation process that requires transcriptional regulation and chromatin reorganization.
After fertilization, the gametes then go through extensive epigenetic reprogramming, which resets the cells to a totipotent state essential for the development of the embryo.
Several histone modifications characterize distinct developmental stages of gamete formation and early embryonic development, but it is unknown whether these modifications have any physiological role.
Furthermore, accumulating evidence suggests that environmentally induced chromatin changes can be inherited, yet the mechanisms underlying zygotic inheritance of the gamete epigenome remain unclear.
This review gives a brief overview of the mechanisms of transgenerational epigenetic inheritance and examines the function of epigenetics during oogenesis and early embryogenesis with a focus on histone posttranslational modifications.
http://bfg.oxfordjournals.org/.....3b7a48f096
Transcriptome dynamics and diversity in an early embryo
doi: 10.1093/bfgp/elt049
Recent years advances in high-throughput sequencing have improved our understanding of how transcripts regulate early vertebrate development.
Here, we review the transcriptome dynamics and diversity during early stages of zebrafish embryogenesis.
Transcriptome dynamics is characterized by different patterns of mRNA degradation, activation of dormant transcripts and onset of transcription.
Several studies have shown a striking diversity of both coding and non-coding transcripts.
However, in the aftermath of this immense increase in data, functional studies of both protein-coding and non-coding transcripts are lagging behind.
We anticipate that the forthcoming years will see studies relying on different high-throughput sequencing technologies and genomic tools developed for zebrafish embryos to further pin down yet un-annotated transcript–function relationships.
http://bfg.oxfordjournals.org/.....3b7a48f096
Molecular Machines at Work
The next Cell Press Webinar will look at structural biology of macromolecular complexes and how structural insights enable deeper functional understanding.
In this webinar, Eva Nogales, Venki Ramakrishnan, and Andrew Ward will discuss some of the most recent successes in solving structures of complex biological systems.
This webinar is for anyone interested in learning about the latest in structural biology as well as different ways that researchers are using structural biology to address various questions related to the cellular function of large biomolecular assemblies.
The webinar is an excellent opportunity to learn what is possible at the cutting edge of structural biology and how it might impact your own research.
http://view6.workcast.net/regi.....9491135649
Wired in
DOI: http://dx.doi.org/10.1016/j.tibs.2014.08.007
In biochemical research, the wiring diagram is the ubiquitous symbol of a signal transduction pathway.
These roadmaps of signaling circuitry reduce complicated protein–protein interaction cascades into simple(r), easy-to-follow summaries.
The wiring of any signal transduction pathway ultimately boils down to a few key steps: the detection and transduction of the signal, amplification of that signal, and integration into a response.
In this Special Issue, TiBS presents a selection of Reviews that focus on our emerging understanding of the molecular mechanisms involved in each of these key steps, and ultimately how they can be subverted and ‘rewired’ in different physiological contexts such as disease.
http://www.cell.com/trends/bio.....14)00150-9
DNA’s security system unveiled
As befitting life’s blueprint, DNA is surrounded by an elaborate security system that assures crucial information is imparted without error.
In a new study appearing in Cell, Yale Univ. researchers Brant Webster, Patrick Lusk and colleagues describe a key quality control mechanism that protects new cells from inheriting defective NPCs.
In the accompanying movie, defective NPCs are sequestered into a specialized compartment (colored red) that is retained in the mother cell, while each daughter inherits functional NPCs.
“It is important to understand how these gatekeepers, which are fundamental to cellular function, are built and maintained,” Lusk said.
http://www.rdmag.com/videos/20.....cation=top
ESCRTs Take on a Job in Surveillance
DOI: http://dx.doi.org/10.1016/j.cell.2014.09.046
Nuclear pore assembly can go awry, but how the cell handles defective intermediates has been an ongoing question.
In this issue, Lusk and colleagues describe a surveillance pathway during nuclear pore assembly and, in doing so, identify a new role for proteins that function at the endosome and plasma membrane.
http://www.cell.com/cell/abstr.....14)01234-3
Control of Cell Identity Genes Occurs in Insulated Neighborhoods in Mammalian Chromosomes
DOI: http://dx.doi.org/10.1016/j.cell.2014.09.030
The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of genes that control cell identity and repression of genes encoding lineage-specifying developmental regulators. Here, we use ESC cohesin ChIA-PET data to identify the local chromosomal structures at both active and repressed genes across the genome. The results produce a map of enhancer-promoter interactions and reveal that super-enhancer-driven genes generally occur within chromosome structures that are formed by the looping of two interacting CTCF sites co-occupied by cohesin. These looped structures form insulated neighborhoods whose integrity is important for proper expression of local genes. We also find that repressed genes encoding lineage-specifying developmental regulators occur within insulated neighborhoods. These results provide insights into the relationship between transcriptional control of cell identity genes and control of local chromosome structure.
•Cohesin ChIA-PET reveals local chromosome structures in the ES cell genome
•Super-enhancer-driven cell identity genes occur in insulated chromosome loops
•Polycomb-bound lineage-specifying genes occur in insulated chromosome loops
•Integrity of insulated neighborhoods is important for normal gene expression
Surveillance of Nuclear Pore Complex Assembly by ESCRT-III/Vps4
DOI: http://dx.doi.org/10.1016/j.cell.2014.09.012
The maintenance of nuclear compartmentalization by the nuclear envelope and nuclear pore complexes (NPCs) is essential for cell function; loss of compartmentalization is associated with cancers, laminopathies, and aging.
We uncovered a pathway that surveils NPC assembly intermediates to promote the formation of functional NPCs.
Surveillance is mediated by Heh2, a member of the LEM (Lap2-emerin-MAN1) family of integral inner nuclear membrane proteins, which binds to an early NPC assembly intermediate, but not to mature NPCs.
Heh2 recruits the endosomal sorting complex required for transport (ESCRT)—III subunit Snf7 and the AAA-ATPase Vps4 to destabilize and clear defective NPC assembly intermediates.
When surveillance or clearance is compromised, malformed NPCs accumulate in a storage of improperly assembled nuclear pore complexes compartment, or SINC.
The SINC is retained in old mothers to prevent loss of daughter lifespan, highlighting a continuum of mechanisms to ensure nuclear compartmentalization.
http://www.cell.com/cell/abstr.....14)01161-1
Long Noncoding RNAs in Cell-Fate Programming and Reprogramming
DOI: http://dx.doi.org/10.1016/j.stem.2014.05.014
In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of regulators of gene expression.
lncRNAs exhibit several distinctive features that confer unique regulatory functions, including exquisite cell- and tissue-specific expression and the capacity to transduce higher-order spatial information.
Here we review evidence showing that lncRNAs exert critical functions in adult tissue stem cells, including skin, brain, and muscle, as well as in developmental patterning and pluripotency.
We highlight new approaches for ascribing lncRNA functions and discuss mammalian dosage compensation as a classic example of an lncRNA network coupled to stem cell differentiation.
DOI
If the provided DOI doesn’t start with ‘http://’ then appending the DOI to the prefix http://dx.doi.org/ should produce a link to the given article.
A Molecular Switch for the Orientation of Epithelial Cell Polarización
DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.027
The formation of epithelial tissues containing lumens requires not only the apical-basolateral polarization of cells, but also the coordinated orientation of this polarity such that the apical surfaces of neighboring cells all point toward the central lumen.
Defects in extracellular matrix (ECM) signaling lead to inverted polarity so that the apical surfaces face the surrounding ECM.
We report a molecular switch mechanism controlling polarity orientation.
ECM signals through a ?1-integrin/FAK/p190RhoGAP complex to downregulate a RhoA/ROCK/Ezrin pathway at the ECM interface.
PKC?II phosphorylates the apical identity-promoting Podocalyxin/NHERF1/Ezrin complex, removing Podocalyxin from the ECM-abutting cell surface and initiating its transcytosis to an apical membrane initiation site for lumen formation.
Inhibition of this switch mechanism results in the retention of Podocalyxin at the ECM interface and the development instead of collective front-rear polarization and motility.
Thus, ECM-derived signals control the morphogenesis of epithelial tissues by controlling the collective orientation of epithelial polarization.
Regulatory Circuit Controls Lipid Droplet Fusion and Growth
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.005
Rab GTPases, by targeting to specific membrane compartments, play essential roles in membrane trafficking.
Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis.
Fsp27 is shown to be required for LD fusion and growth by enriching at LD-LD contact sites.
Here, we identify Rab8a as a direct interactor and regulator of Fsp27 in mediating LD fusion in adipocytes.
Knockdown of Rab8a in the livers of ob/ob mice results in the accumulation of smaller LDs and lower hepatic lipid levels.
Surprisingly, it is the GDP-bound form of Rab8a that exhibits fusion-promoting activity.
We further discover AS160 as the GTPase activating protein (GAP) for Rab8a, which forms a ternary complex with Fsp27 and Rab8a to positively regulate LD fusion.
MSS4 antagonizes Fsp27-mediated LD fusion activity through Rab8a.
Our results have thus revealed a mechanistic signaling circuit controlling LD fusion and fatty liver formation.
Cutting through the Noise: The Mechanics of Intracellular Transport
DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.013
Intracellular transport of organelles and proteins is driven by multiple ATP-dependent processes.
Recently in Cell, Guo et al. (2014) developed a technique, force-spectrum microscopy, to measure intracellular forces and demonstrate that large motion of cellular components can be produced by random ATP-dependent fluctuations within the cytoplasm.
The Architecture of CCAN Proteins Creates a Structural Integrity to Resist Spindle Forces and Achieve Proper Intrakinetochore Stretch
DOI: http://dx.doi.org/10.1016/j.devcel.2014.08.003
Constitutive centromere-associated network (CCAN) proteins, particularly CENP-C, CENP-T, and the CENP-H/-I complex, mechanically link CENP-A-containing centromeric chromatin within the inner kinetochore to outer kinetochore proteins, such as the Ndc80 complex, that bind kinetochore microtubules.
Accuracy of chromosome segregation depends critically upon Aurora B phosphorylation of Ndc80/Hec1.
To determine how CCAN protein architecture mechanically constrains intrakinetochore stretch between CENP-A and Ndc80/Hec1 for proper Ndc80/Hec1 phosphorylation, we used super-resolution fluorescence microscopy and selective protein depletion.
We found that at bi-oriented chromosomes in late prometaphase cells, CENP-T is stretched ?16 nm to the inner end of Ndc80/Hec1, much less than expected for full-length CENP-T.
Depletion of various CCAN linker proteins induced hyper-intrakinetochore stretch (an additional 20–60 nm) with corresponding significant decreases in Aurora B phosphorylation of Ndc80/Hec1.
Thus, proper intrakinetochore stretch is required for normal kinetochore function and depends critically on all the CCAN mechanical linkers to the Ndc80 complex.
Combining Genetic Perturbations and Proteomics to Examine Kinase-Phosphatase Networks
DOI: http://dx.doi.org/10.1016/j.devcel.2014.07.027
Connecting phosphorylation events to kinases and phosphatases is key to understanding the molecular organization and signaling dynamics of networks.
We have generated a validated set of transgenic RNA-interference reagents for knockdown and characterization of all protein kinases and phosphatases present during early Drosophila melanogaster development.
These genetic tools enable collection of sufficient quantities of embryos depleted of single gene products for proteomics.
As a demonstration of an application of the collection, we have used multiplexed isobaric labeling for quantitative proteomics to derive global phosphorylation signatures associated with kinase-depleted embryos to systematically link phosphosites with relevant kinases.
We demonstrate how this strategy uncovers kinase consensus motifs and prioritizes phosphoproteins for kinase target validation.
We validate this approach by providing auxiliary evidence for Wee kinase-directed regulation of the chromatin regulator Stonewall.
Further, we show how correlative phosphorylation at the site level can indicate function, as exemplified by Sterile20-like kinase-dependent regulation of Stat92E.
How Kinetochores CCAN Resist Force
DOI: http://dx.doi.org/10.1016/j.devcel.2014.09.007
Kinetochores orchestrate chromosome segregation during mitosis and must cope with dynamic forces generated by attached microtubules.
In this issue of Developmental Cell, Suzuki et al. (2014) demonstrate that the constitutive centromere-associated network (CCAN) displays a complex architecture that plays a crucial role in resisting these forces.
Global Programmed Switch in Neural Daughter Cell Proliferation Mode Triggered by a Temporal Gene Cascade
DOI: http://dx.doi.org/10.1016/j.devcel.2014.06.021
During central nervous system (CNS) development, progenitors typically divide asymmetrically, renewing themselves while budding off daughter cells with more limited proliferative potential.
Variation in daughter cell proliferation has a profound impact on CNS development and evolution, but the underlying mechanisms remain poorly understood.
We find that Drosophila embryonic neural progenitors (neuroblasts) undergo a programmed daughter proliferation mode switch, from generating daughters that divide once (type I) to generating neurons directly (type 0).
This typeI>0 switch is triggered by activation of Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2) expression in neuroblasts.
In the thoracic region, Dacapo expression is activated by the temporal cascade (castor) and the Hox gene Antennapedia.
In addition, castor, Antennapedia, and the late temporal gene grainyhead act combinatorially to control the precise timing of neuroblast cell-cycle exit by repressing Cyclin E and E2f.
This reveals a logical principle underlying progenitor and daughter cell proliferation control in the Drosophila CNS.
The promise of organotypic models
DOI: http://dx.doi.org/10.1016/j.tibtech.2014.04.006
Advances in the design and assembly of in vitro organotypic liver and gastrointestinal (GI) models can accelerate our understanding of metabolism, nutrient absorption, and the effect of microbial flora.
Such models can provide comprehensive information on how of environmental toxins, drugs, and pharmaceuticals interact with and within these organs.
Information obtained from such models could elucidate the complicated cascades of signaling mechanisms that occur in vivo.
Because experiments on large-scale animal models are expensive and resource intensive, the design of organotypic models has renewed significance.
The challenges and approaches to designing liver and GI models are similar.
Because these organs are in close proximity and interact continually, we have described recent design considerations to guide future tissue models.
A Quantitative Framework to Evaluate Modeling of Cortical Development by Neural Stem Cells
DOI: http://dx.doi.org/10.1016/j.neuron.2014.05.035
Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro.
However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner.
We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs).
Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease.
We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models.
We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories.
This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
The 3D Genome in Transcriptional Regulation and Pluripotency
DOI: http://dx.doi.org/10.1016/j.stem.2014.05.017
It can be convenient to think of the genome as simply a string of nucleotides, the linear order of which encodes an organism’s genetic blueprint.
However, the genome does not exist as a linear entity within cells where this blueprint is actually utilized.
Inside the nucleus, the genome is organized in three-dimensional (3D) space, and lineage-specific transcriptional programs that direct stem cell fate are implemented in this native 3D context.
Here, we review principles of 3D genome organization in mammalian cells.
We focus on the emerging relationship between genome organization and lineage-specific transcriptional regulation, which we argue are inextricably linked.
Endoderm Generates Endothelial Cells during Liver Development
DOI: http://dx.doi.org/10.1016/j.stemcr.2014.08.009
Organogenesis requires expansion of the embryonic vascular plexus that migrates into developing organs through a process called angiogenesis.
Mesodermal progenitors are thought to derive endothelial cells (ECs) that contribute to both embryonic vasculogenesis and the subsequent organ angiogenesis.
Here, we demonstrate that during development of the liver, which is an endoderm derivative, a subset of ECs is generated from FOXA2+ endoderm-derived fetal hepatoblast progenitor cells expressing KDR (VEGFR2/FLK-1).
Using human and mouse embryonic stem cell models, we demonstrate that KDR+FOXA2+ endoderm cells developing in hepatic differentiation cultures generate functional ECs.
This introduces the concept that ECs originate not exclusively from mesoderm but also from endoderm, supported in Foxa2 lineage-tracing mouse embryos by the identification of FOXA2+ cell-derived CD31+ ECs that integrate the vascular network of developing fetal livers.
Neural Stem Cell Differentiation Is Dictated by Distinct Actions of Nuclear Receptor Corepressors and Histone Deacetylases
DOI: http://dx.doi.org/10.1016/j.stemcr.2014.07.008
Signaling factors including retinoic acid (RA) and thyroid hormone (T3) promote neuronal, oligodendrocyte, and astrocyte differentiation of cortical neural stem cells (NSCs).
However, the functional specificity of transcriptional repressor checkpoints controlling these differentiation programs remains unclear.
Here, we show by genome-wide analysis that histone deacetylase (HDAC)2 and HDAC3 show overlapping and distinct promoter occupancy at neuronal and oligodendrocyte-related genes in NSCs.
The absence of HDAC3, but not HDAC2, initiated a neuronal differentiation pathway in NSCs.
The ablation of the corepressor NCOR or HDAC2, in conjunction with T3 treatment, resulted in increased expression of oligodendrocyte genes, revealing a direct HDAC2-mediated repression of Sox8 and Sox10 expression.
Interestingly, Sox10 was required also for maintaining the more differentiated state by repression of stem cell programming factors such as Sox2 and Sox9.
Distinct and nonredundant actions of NCORs and HDACs are thus critical for control of lineage progression and differentiation programs in neural progenitors.
A Dynamic Microtubule Cytoskeleton Directs Medial Actomyosin Function during Tube Formation
DOI: http://dx.doi.org/10.1016/j.devcel.2014.03.023
The cytoskeleton is a major determinant of cell-shape changes that drive the formation of complex tissues during development.
Important roles for actomyosin during tissue morphogenesis have been identified, but the role of the microtubule cytoskeleton is less clear.
Here, we show that during tubulogenesis of the salivary glands in the fly embryo, the microtubule cytoskeleton undergoes major rearrangements, including a 90° change in alignment relative to the apicobasal axis, loss of centrosomal attachment, and apical stabilization.
Disruption of the microtubule cytoskeleton leads to failure of apical constriction in placodal cells fated to invaginate.
We show that this failure is due to loss of an apical medial actomyosin network whose pulsatile behavior in wild-type embryos drives the apical constriction of the cells.
The medial actomyosin network interacts with the minus ends of acentrosomal microtubule bundles through the cytolinker protein Shot, and disruption of Shot also impairs apical constriction.
Brain’s Compass Relies on Geometric Relationships
http://www.biosciencetechnolog.....cation=top
549 follow-up
Anchoring the neural compass: coding of local spatial reference frames in human medial parietal lobe
doi:10.1038/nn.3834
The neural systems that code for location and facing direction during spatial navigation have been investigated extensively; however, the mechanisms by which these quantities are referenced to external features of the world are not well understood.
To address this issue, we examined behavioral priming and functional magnetic resonance imaging activity patterns while human subjects recalled spatial views from a recently learned virtual environment.
Behavioral results indicated that imagined location and facing direction were represented during this task, and multivoxel pattern analyses indicated that the retrosplenial complex (RSC) was the anatomical locus of these spatial codes.
Critically, in both cases, location and direction were defined on the basis of fixed elements of the local environment and generalized across geometrically similar local environments.
These results suggest that RSC anchors internal spatial representations to local topographical features, thus allowing us to stay oriented while we navigate and retrieve from memory the experience of being in a particular place.
http://www.nature.com/neuro/jo......3834.html
Haematopoietic stem cells, niches and differentiation pathways
Thomas Graf and Andreas Trumpp
Haematopoietic stem cells (HSCs) are characterized by extensive self-renewal capacity and the ability to differentiate into multiple cell lineages of the immune system.
Much current research is focused on understanding the nature of HSC niches and the molecular interactions between cells in these niches.
The nature of the early stages of HSC development is also a hot topic in the HSC field.
This poster provides an overview of HSC niches, including details of the molecules that mediate interactions between HSCs, osteoblasts and CXCL12-expressing reticular cells in these niches.
The differentiation pathways of HSC-derived cells of the immune system are also illustrated, including the lineage-instructive factors that mediate each developmental stage.
The poster is freely available thanks to support from Abcam.
http://www.nature.com/nri/posters/hsc/index.html
Molecular mechanisms of stem-cell identity and fate
Fiona M. Watt and Kevin Eggan
Stem cells have been identified and characterized in several mammalian tissues.
In addition, pluripotent embryonic stem cells have been derived from pre-implantation embryos in both mice and humans.
Whereas the recent advances in stem-cell research have the potential to revolutionize medicine, the critical scientific challenge remains to elucidate the fundamental cellular and molecular controls of stem cells.
An understanding of the molecular mechanisms that govern stem-cell fate and the identification of specific stem-cell markers is of fundamental significance in cell and developmental biology.
This Poster provides an overview of distinct embryonic and adult stem-cell types and the stem-cell markers that have been used to identify stem cells and cancer-stem-cell-enriched populations.
The Poster is freely available thanks to support from Abcam.
View this poster as a high-resolution PDF (2,855 KB)
http://www.nature.com/nrc/post.....index.html
Pathways represented as a subway map
[kind of old, but still interesting poster]
http://www.nature.com/nrc/post.....index.html
In a biological system so many things can easily mess things up that I’m amazed the whole thing still works so many times.
http://www.nature.com/nrc/post.....index.html
important constraints on models of the neuronal mechanisms underlying cognitive factors
Attention can either increase or decrease spike count correlations in visual cortex
doi:10.1038/nn.3835
Visual attention enhances the responses of visual neurons that encode the attended location.
Several recent studies have shown that attention also decreases correlations between fluctuations in the responses of pairs of neurons (termed spike count correlation or rSC).
These results are consistent with two hypotheses.
First, attention-related changes in rate and rSC might be linked (perhaps through a common mechanism), with attention always decreasing rSC.
Second, attention might either increase or decrease rSC, possibly depending on the role of the neurons in the behavioral task.
We recorded simultaneously from dozens of neurons in area V4 while monkeys performed a discrimination task.
We found strong evidence in favor of the second hypothesis, showing that attention can flexibly increase or decrease correlations depending on whether the neurons provide evidence for the same or opposite choices.
These results place important constraints on models of the neuronal mechanisms underlying cognitive factors.
http://www.nature.com/neuro/jo......3835.html
Genome-wide identification and characterization of functional neuronal activity–dependent enhancers
doi:10.1038/nn.3808
Experience-dependent gene transcription is required for nervous system development and function.
However, the DNA regulatory elements that control this program of gene expression are not well defined.
Here we characterize the enhancers that function across the genome to mediate activity-dependent transcription in mouse cortical neurons.
We find that the subset of enhancers enriched for monomethylation of histone H3 Lys4 (H3K4me1) and binding of the transcriptional coactivator CREBBP (also called CBP) that shows increased acetylation of histone H3 Lys27 (H3K27ac) after membrane depolarization of cortical neurons functions to regulate activity-dependent transcription.
A subset of these enhancers appears to require binding of FOS, which was previously thought to bind primarily to promoters.
These findings suggest that FOS functions at enhancers to control activity-dependent gene programs that are critical for nervous system function and provide a resource of functional cis-regulatory elements that may give insight into the genetic variants that contribute to brain development and disease.
http://www.nature.com/neuro/jo......3808.html
Information-limiting correlations
doi:10.1038/nn.3807
Computational strategies used by the brain strongly depend on the amount of information that can be stored in population activity, which in turn strongly depends on the pattern of noise correlations.
In vivo, noise correlations tend to be positive and proportional to the similarity in tuning properties.
Such correlations are thought to limit information, which has led to the suggestion that decorrelation increases information.
In contrast, we found, analytically and numerically, that decorrelation does not imply an increase in information.
Instead, the only information-limiting correlations are what we refer to as differential correlations: correlations proportional to the product of the derivatives of the tuning curves.
Unfortunately, differential correlations are likely to be very small and buried under correlations that do not limit information, making them particularly difficult to detect.
We found, however, that the effect of differential correlations on information can be detected with relatively simple decoders.
http://www.nature.com/neuro/jo......3807.html
Proteogenomics: Integrating Proteomics and Genomics to Unlock Biological Function
http://www.genengnews.com/insi...../77900284/
Stem Cells Defy Germ Layer Destiny
http://www.genengnews.com/gen-...../81250479/
Illuminating the Multifaceted Roles of Neurotransmission in Shaping Neuronal Circuitry
DOI: http://dx.doi.org/10.1016/j.neuron.2014.08.029
Across the nervous system, neurons form highly stereotypic patterns of synaptic connections that are designed to serve specific functions.
Mature wiring patterns are often attained upon the refinement of early, less precise connectivity.
Much work has led to the prevailing view that many developing circuits are sculpted by activity-dependent competition among converging afferents, which results in the elimination of unwanted synapses and the maintenance and strengthening of desired connections.
Studies of the vertebrate retina, however, have recently revealed that activity can play a role in shaping developing circuits without engaging competition among converging inputs that differ in their activity levels.
Such neurotransmission-mediated processes can produce stereotypic wiring patterns by promoting selective synapse formation rather than elimination.
We discuss how the influence of transmission may also be limited by circuit design and further highlight the importance of transmission beyond development in maintaining wiring specificity and synaptic organization of neural circuits.
Stem Cell Peaks Yet Unscaled
http://www.genengnews.com/gen-.....19/?page=1
Structural Choreography of Cellular Self-Digestion
http://www.mskcc.org/events/se.....-Digestion
Structural biology seeks to provide a complete and coherent picture of biological phenomena at the molecular and atomic level.
The goals of structural biology include developing a comprehensive understanding of the molecular shapes and forms embraced by biological macromolecules and extending this knowledge to understand how different molecular architectures are used to perform the chemical reactions that are central to life.
In addition, structural biologists are interested in understanding related processes such as protein folding, protein dynamics, molecular modeling, drug design, and computational biology.
Central tools used in this research include X-ray diffraction, NMR, electron microscopy, other spectroscopies and biophysical methods, protein expression, bio-physical and bio-organic chemistry, computer science and bioengineering.
https://biology.mit.edu/research/structural_biology
Structural Biology Research
Members of Princeton’s vibrant structural biology community—students, postdocs, and faculty—make use of a wide array of cutting-edge methods to gain insight into biological structure and mechanism.
Some examples of the approaches being used, and in some cases developed, at Princeton include x-ray crystallography, electron microscopy, mass spectrometry, NMR spectroscopy, super-resolution optical microscopy, single-molecule methods, and computational modeling.
These tools are being applied to biological problems ranging from protein folding and design, to signal transduction, to intracellular trafficking.
Structural biology is an intrinsically interdisciplinary activity; Princeton provides a supportive and exceptionally collegial environment for students to receive training in these areas while, at the same time, contributing to fundamental discoveries about form and function in the biological world.
http://molbio.princeton.edu/fa.....al-biology
Transcriptional Switches During Development
http://www.elsevier.com/books/.....2-386499-4
Sertoli Cell Biology
http://www.sciencedirect.com/s.....0126477511
#565 addendum
Transcriptional Switches During Development
The general concepts of transcriptional regulation are now well established, a major challenge resides in understanding the logic and physical elements implementing these regulatory interactions within a given cell in a developing organism.
A central problem to be addressed is how transcriptional programs are set up and then modified throughout the successive steps of embryonic development.
The book Transcriptional Switches during Development provides a broad range of insights into the molecular determinants of such transcriptional switches during development.
It summarizes efforts to tackle this question in various model systems, each with their advantages and limitations.
These contributions also show that different scales of analysis are required together to solve the problem of gene expression control during development.
It is believed that the combination of both genome-wide approaches (experimental or predictive) and functional analyses scrutinizing the intimate details of each element is the most promising way to unravel the control of terminal differentiation and its evolutionary diversification.
Computational Systems Biology
http://www.sciencedirect.com/s.....0124059269
Genomic Control Process
Genomic Control Process explores the biological phenomena around genomic regulatory systems that control and shape animal development processes, and which determine the nature of evolutionary processes that affect body plan.
Unifying and simplifying the descriptions of development and evolution by focusing on the causality in these processes, it provides a comprehensive method of considering genomic control across diverse biological processes.
This book is essential for graduate researchers in genomics, systems biology and molecular biology seeking to understand deep biological processes which regulate the structure of animals during development.
Covers a vast area of current biological research to produce a genome oriented regulatory bioscience of animal life
Places gene regulation, embryonic and postembryonic development, and evolution of the body plan in a unified conceptual framework
Provides the conceptual keys to interpret a broad developmental and evolutionary landscape with precise experimental illustrations drawn from contemporary literature
Includes a range of material, from developmental phenomenology to quantitative and logic models, from phylogenetics to the molecular biology of gene regulation, from animal models of all kinds to evidence of every relevant type
Demonstrates the causal power of system-level understanding of genomic control process
Contents
1. The Genome in Development
2. Gene Regulatory Networks
3. Genomic Strategies for Embryonic Development
4. Genomic Control Processes in Adult Body Part Formation
5. Genomic Strategies for Cell Fate Determination
6. Predictive Gene Regulatory Network Models
7. Evolution of Bilaterian Animals: Processes of Change and Stasis in Hierarchical Development