Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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How MTs achieve reliable chromosome segregation has been a mystery ever since it was clear that MTs constitute the mitotic spindle. How MTs can be organized into the spindle shape, display these dynamics, and effectively segregate chromosomes has remained mysterious. But how could a spindle be formed if its core constituents are intrinsically unstable? [...] an accurate description of the molecular building plan will require new methods to directly measure parameters that are key to explaining various features of MT organization [...] The precise organization of MTs during spindle assembly remains to be determined [...] The specific factors in these organisms that influence spindle shape, however, still need to be established.
Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity.Dionisio_{December 29, 2016
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The MT lattice can also be allosterically regulated by MAPs, which do not directly contact each other, adding a new layer of complexity to the modes of how MAPs can modulate MT dynamics [...] [...] future studies need to take these functional assemblies into account. [...] the next major challenge is to understand how these MAPs work together with MTs at the nanometer scale to assemble the mitotic spindle, which is a factor of 1,000 larger than its constituents, and to orchestrate chromosome segregation, as discussed in the next section.
Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity.Dionisio_{December 29, 2016
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As of now, information about a particular spindle MAP still has to be looked up in each separately published database. Hence, a necessary future step to maximize the impact of these valuable studies is their integration into a unified spindle genome and proteome database. It remains to be determined which effectors induce this conformational change, whether ring closure is the only mode of catalysis, and whether this also applies to the larger ?-TuRC. [...] how tubulin dimers are assembled into a tubule from the ?-TuRC base is still unknown [...] [...] it is unclear whether MT minus-end proteins other than ?-TuRC also harbor MT nucleation activity [...]
Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity.Dionisio_{December 29, 2016
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Life depends on cell proliferation. This occurs via cell division, during which a single cell generates two daughters, each of which retains the same genetic blueprint packaged into chromosomes via reliable chromosome segregation. [...] several aspects make the mitotic spindle one of the most challenging systems to grasp at quantitative and molecular levels. [...] understanding the exact mechanisms of spindle assembly and chromosome segregation has been complicated by our inability to accurately determine the location of its macromolecular components in space and time. [...] advanced methods for probing MT organization in the metaphase spindle have yet to be applied to determine the molecular mechanisms by which chromosomes are captured, aligned, and reliably segregated during cell division.
Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity.Dionisio_{December 29, 2016
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Life depends on cell proliferation and the accurate segregation of chromosomes, which are mediated by the microtubule (MT)-based mitotic spindle and ~200 essential MT-associated proteins. Yet, a mechanistic understanding of how the mitotic spindle is assembled and achieves chromosome segregation is still missing. [...] mechanistic details about MT nucleation pathways and their coordination are starting to be revealed. [...] advances in studying spindle assembly can be applied to address the molecular mechanisms of how the spindle segregates chromosomes.
Mechanisms of Mitotic Spindle Assembly. Petry S Annu Rev Biochem. 85:659-83. doi: 10.1146/annurev-biochem-060815-014528

Complex complexity.Dionisio_{December 29, 2016
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[...] KLP-18 and MESP-1 are required to provide an outward force to sort microtubule minus ends away from the chromosomes, enabling bipolar spindle formation. Future work determining the mechanisms by which KLP-18 and MESP-1 act to organize microtubules and generate bipolarity will shed light on this important but poorly understood specialized cell division, as well as on overall kinesin-12 function during cell division.
Assembly of Caenorhabditis elegans acentrosomal spindles occurs without evident microtubule-organizing centers and requires microtubule sorting by KLP-18/kinesin-12 and MESP-1. Wolff ID Tran MV, Mullen TJ, Villeneuve AM, Wignall SM Mol Biol Cell. 27(20):3122-3131. DOI: 10.1091/mbc.E16-05-0291

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Although centrosomes contribute to spindle formation in most cell types, oocytes of many species are acentrosomal and must organize spindles in their absence. [...] KLP-18/kinesin-12 and MESP-1 form a complex that functions to sort microtubules of mixed polarity into a configuration in which minus ends are away from the chromosomes, enabling formation of nascent poles. [...] spindle assembly proceeds through 1) formation of a disordered array of microtubules within the remnants of the nuclear envelope, 2) sorting of microtubule minus ends away from the chromosomes to the periphery of the array, 3) organization of these ends into nascent poles, and 4) progressive coalescence of these poles until bipolarity is achieved.
Assembly of Caenorhabditis elegans acentrosomal spindles occurs without evident microtubule-organizing centers and requires microtubule sorting by KLP-18/kinesin-12 and MESP-1. Wolff ID Tran MV, Mullen TJ, Villeneuve AM, Wignall SM Mol Biol Cell. 27(20):3122-3131. DOI: 10.1091/mbc.E16-05-0291

Evident algorithmic process. Complex complexity.Dionisio_{December 29, 2016
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More extensive genetic studies that simultaneously reduce the function of different combinations of these alternative pathways may clarify how they are integrated to execute meiotic cell division. [...] a thorough understanding of the pleiotropic functions of these proteins will likely require techniques that selectively inactivate individual proteins in specific subcellular regions at specific times. Given recent advances in optogenetics, such approaches may soon become possible. [...] the molecular pathways that mediate meiotic spindle assembly appear to be numerous and diverse. To advance our understanding, more systematic genetic analyses are needed. The challenges to achieving a conclusive mechanistic understanding of meiotic spindle assembly and function in any one system extend well beyond a need for further genetic studies. The pace of progress in this field has picked up considerably in the past five years, and recent advances in genetics and microscopy make rapid and significant further progress imminent.
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Work in progress... stay tuned. Complex complexity.Dionisio_{December 28, 2016
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It will be interesting to test whether MCAK-mediated removal of improper microtubule–kinetochore attachments is important for oocyte spindle pole coalescence in other organisms. Whether the apparent lack of a substantial role for kinetochores during anaphase in C. elegans oocytes is relevant to other species is not known. Systematic investigations of how microtubule–kinetochore attachments, and kinetochore function more generally, influence spindle assembly and chromosome movement are needed to fully assess and compare the role of these structures during oocyte meiotic cell division in different animal species.
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity.Dionisio_{December 28, 2016
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The absence of centrosomes and their impressive microtubule organizing activity leaves a mechanistic void in our understanding of how oocyte spindles achieve the bipolar structure required to segregate chromosomes in opposite directions. How the multiple, dispersed MTOCs coalesce to form two poles remains unknown. [...] how ZYG-9 influences oocyte spindle assembly is not well understood and the role of TAC-1 has not been addressed. [...] systematic comparisons of the different gene requirements in each model system are needed to better assess the conservation, and divergence of oocyte spindle assembly mechanisms. [...] the mechanism of MTOC coalescence remains unknown. [...] the importance of microtubule–kinetochore attachment for oocyte spindle assembly in other species remains largely unknown [...]
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity.Dionisio_{December 28, 2016
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The role of ?-tubulin during oocyte spindle assembly clearly warrants further investigation. Whether these other processes contribute to oocyte meiotic spindle assembly remains poorly understood. [...] it seems likely that multiple pathways contribute to microtubule nucleation and organization during oocyte meiosis, although the relative importance of each pathway may vary from organism to organism. While a gradient of active Ran GTPase can stimulate microtubule assembly around chromosomes, where and how nucleation occurs is not clear. [...] how microtubules are nucleated at more distant sites and are then transported toward the spindle remain poorly understood and are ripe topics for further investigation.
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

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[...] mitotic and oocyte meiotic spindles have remarkably distinct structures and dynamics. Why oocyte meiotic spindles should be composed of short, discontinuous microtubules is not known [...] [...] understanding the origin of oocyte meiotic spindle microtubules is of fundamental importance. [...] it remains unclear whether the CPC pathway requires ?-tubulin [...]
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

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[...] the zygote inherits one maternal centrosome with a single, unduplicated centriole and one paternal centrosome with a duplicated centriole. While the fate of the remaining oocyte centrosome is unknown, subsequent mitotic divisions use the sperm-derived centrioles [...]
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity.Dionisio_{December 28, 2016
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A nearly universal feature of animal life is the fusion of two haploid gametes to create a diploid zygote. Most animal cells except gametes have two closely related but genetically distinct copies of each chromosome, called homologous chromosome pairs, one inherited from each parent. The fundamental achievement of gametogenesis is to reduce the diploid genome of germline precursors to a haploid state through two specialized cell divisions, called meiosis I and II [...] When two gamete genomes unite after the fertilization of an egg by a sperm, diploidy is restored and life begins anew.
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

life begins anew? Did somebody say "life begins"? Did they mean it does at fertilization? Are they serious? Did I get this right? Complex complexity.Dionisio_{December 28, 2016
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Gametogenesis in animal oocytes reduces the diploid genome content of germline precursors to a haploid state in gametes by discarding ¾ of the duplicated chromosomes through a sequence of two meiotic cell divisions called meiosis I and II. The assembly of the microtubule-based spindle structure that mediates this reduction in genome content remains poorly understood [...]
Oocyte Meiotic Spindle Assembly and Function. Severson AF, von Dassow G, Bowerman B Curr Top Dev Biol. 116:65-98. doi: 10.1016/bs.ctdb.2015.11.031.

Complex complexity.Dionisio_{December 28, 2016
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The centrosome, an organelle discovered >100 years ago, is the main microtubule-organizing center in mammalian organisms. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material (PMC) and plays a major role in the regulation of cell cycle transitions (G1-S, G2-M, and metaphase-anaphase), ensuring the normality of cell division. Hundreds of proteins found in the centrosome exert a variety of roles, including microtubule dynamics, nucleation, and kinetochore-microtubule attachments that allow correct chromosome alignment and segregation. The many associated proteins found in the centrosome orchestrate the control of microtubule nucleation and organization for the proper progression of cell cycle.
Centrosome - a promising anti-cancer target. Rivera-Rivera Y, Saavedra HI Biologics. 10:167-176. doi: 10.2147/BTT.S87396.

orchestrate the control? Did somebody say "orchestrate"? Did somebody say "control"? :) Complex complexity.Dionisio_{December 28, 2016
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[...] the RDNF circuit might have a crucial role in early differentiation during development since the double-negative feedback loop may interpret information regarding the temporal dynamics of morphogen fluctuation to elaborately decide the cell fate [...] [...] the double-negative feedback mechanism can be obtained in different ways in different biological contexts, and it can provide a general mechanism for controlling the cell-fate decision. [...] the cell can respond differently according to the temporal pattern of stimulation even though the final concentrations are unchanged, which suggests that the delivery mode is important in determining the effect of the molecules.
A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

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[...] the mutual inhibitory genetic network having a single input can convert a graded signal into an on/off binary output [...] [...] an interlinked multiple negative feedback mechanism is capable of pre-steady-state decoding a spatial gradient signal to expression of different target genes [...] [...] the double-negative feedback network that was derived from the EPNF can interpret the rate change of an input signal to different response profiles of target proteins before the signal converge to a steady state.
A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

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[...] the regulated double-negative feedback (RDNF) circuit performs the function of temporal gradient-sensitive switching. [...] this regulated double-negative feedback is a hidden design principle enabling cells to decode the information that is encoded in the temporal gradient of an input signal.
A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

hidden design principle? Did somebody say "design"? :) Complex complexity.Dionisio_{December 28, 2016
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How the signaling network encodes and decodes the biological information and what mechanism underlies this process have been a fundamental question in biology [...] our findings bring a new insight into how cells interpret the time-varying cellular environment which they might continuously encounter. Decoding the temporal gradient of input stimulation provides cells with additional useful information about the environment. [...] cells can detect a rapid increase of a toxic molecule’s concentration and cope with it by activating a protection pathway in advance. [...] cells can respond appropriately to a constitutive or regulated secretory mode of molecules by decoding the temporal gradient [...] For a further study, it would be interesting to investigate the possibility of the temporal gradient decoding mechanism with respect to cellular recognition of the frequency of an oscillating signal.
A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity.Dionisio_{December 28, 2016
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Revealing the hidden mechanism of how cells sense and react to environmental signals has been a central question in cell biology. Our analysis highlights the essential structure and mechanism enabling cells to properly respond to dynamic environmental changes. For survival, cells should continuously sense and process signals to make an appropriate decision under dynamically fluctuating cellular environments [...]. They encode biological information on the identity and quantity of a stimulus in different forms of patterns, for instance, amplitude, frequency, and duration of a stimulus [...]. Such information is decoded and interpreted by specific signaling networks (or circuits) to generate a specific cellular response [...].
A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network Sang-Min Park, Sung-Young Shin and Kwang-Hyun Cho PLoS One. 11(9): e0162153. doi: 10.1371/journal.pone.0162153

Complex complexity.Dionisio_{December 28, 2016
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Oocytes accumulate maternal stores (proteins, mRNAs, metabolites, etc.) during their growth in the ovary to support development after fertilization. To preserve this cytoplasmic maternal inheritance, they accomplish the difficult task of partitioning their cytoplasm unequally while dividing their chromosomes equally. Added to this complexity, most oocytes, for reasons still speculative, lack the major microtubule organizing centers that most cells use to assemble and position their spindles, namely canonical centrosomes. The challenge of oocyte divisions appears indeed not trivial because in both mice and humans oocyte meiotic divisions are prone to chromosome segregation errors, a leading cause of frequent miscarriages and congenital defects. It might be so that the critical concentration for tubulin to polymerize might be much more difficult to reach than in somatic cells when the nucleus breaks down, reinforcing the importance of pathways acting as catalyzers/amplifiers of tubulin polymerization locally around chromosomes. How these pathways, and yet-to-be-discovered ones, interact to promote early stages of spindle assembly has not been thoroughly addressed and remains an important question for future studies.
Meiotic spindle assembly and chromosome segregation in oocytes. Bennabi I, Terret ME, Verlhac MH Cell Biol. 215(5):611-619. DOI: 10.1083/jcb.201607062

Had we stayed in Eden none of this would have been an issue. Too late now. The whole system is messed up badly. Complex complexity.Dionisio_{December 27, 2016
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Although centriole elimination has been studied in many species, the underlying mechanisms are far from being understood. [...] centriole elimination from the oocyte is essential for sexual reproduction of animal species, but the underlying mechanisms are very poorly understood. It will be interesting in the future to test a possible conservation of molecular mechanisms between these processes. [...] mother and daughter centrioles rely on distinct mechanisms for elimination.
Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes. Borrego-Pinto J, Somogyi K, Karreman MA, König J, Müller-Reichert T, Bettencourt-Dias M, Gönczy P, Schwab Y, Lénárt J Cell Biol. 212(7):815-27. doi: 10.1083/jcb.201510083.

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Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. [...] mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization.
Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes. Borrego-Pinto J, Somogyi K, Karreman MA, König J, Müller-Reichert T, Bettencourt-Dias M, Gönczy P, Schwab Y, Lénárt J Cell Biol. 212(7):815-27. doi: 10.1083/jcb.201510083.

Complex complexity.Dionisio_{December 27, 2016
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[...] what underlies the asymmetry in behavior between the mother and daughter centrioles at anaphase I remains to be discovered. The origin of the difference in behavior between mother and daughter centrioles after anaphase II will require further investigation. To explain the loss in nucleation capacity of the daughter centriole, it will be important to check for the presence of various PCM components. It will be interesting to determine whether starfish zygotes express proteins such as HURP or HSET, which are major players in extra-centrosome clustering [...] [...] maternal centrioles must be extruded from or inactivated in the starfish egg before fertilization so that they do not perturb mitotic spindle assembly.
Mother centrioles are kicked out so that starfish zygote can grow. Verlhac MH J Cell Biol. 212(7):759-61. doi: 10.1083/jcb.201602053.

Work in progress... stay tuned. Complex complexity.Dionisio_{December 27, 2016
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Most oocytes eliminate their centrioles during meiotic divisions through unclear mechanisms. The biological significance of oocyte centriole riddance remains a mystery. [...] mother centrioles need to be eliminated from starfish oocytes by extrusion into the polar bodies for successful embryo development. [...] the pathway leading to centriole elimination has not been identified [...] Whether the mother centriole migrates to the cortex with its appendages facing or opposite the plasma membrane has not been addressed. It would be interesting to assess whether astral microtubules emanating from the mother centriole progressively depolymerize as the mother centriole approaches the plasma membrane to allow the intimate anchoring of the appendages with the plasma membrane. Future work will tell us why the daughter centriole does not experience such a migration event.
Mother centrioles are kicked out so that starfish zygote can grow. Verlhac MH J Cell Biol. 212(7):759-61. doi: 10.1083/jcb.201602053.

Work in progress... stay tuned. Complex complexity.Dionisio_{December 27, 2016
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Looking back... @234, 442, 673: three different comments on the same paper:
Centrosomes back in the limelight Michel Bornens, Pierre Gönczy DOI: 10.1098/rstb.2013.0452 Philos Trans R Soc Lond B Biol Sci. 369(1650).
That was then, what's the latest on this now?Dionisio_{December 27, 2016
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[...] centriole and centrosome transmission is still not understood. Neither the molecules involved, nor even precise terminologies are agreed upon. Deciphering the centriole’s molecular architecture raises questions as to how this miniscule structure manages to organize the entire three-dimensional MT cytoskeleton. More challenges, recently insurmountable, can now be addressed. Within the seemingly rigid confines of a dozen or so uniform building blocks, centrioles enable incredible microtubule diversity, which forms the basis for cellular architecture and motility, thereby enabling development and differentiation.
LEGOs® and legacies of centrioles and centrosomes Gerald Schatten and Calvin Simerly EMBO Rep. 16(9): 1052–1054. doi: 10.15252/embr.201540875

Work in progress... stay tuned. Complex complexity.Dionisio_{December 27, 2016
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A Regulated Double-Negative Feedback Decodes the Temporal Gradient of Input Stimulation in a Cell Signaling Network. Park SM1, Shin SY1,2,3, Cho KH1. PLoS One. 2016 Sep 1;11(9):e0162153m. doi: 10.1371/journal.pone.0162153Dionisio_{December 25, 2016
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Origin of the hematopoietic system in the human embryo Emmanuelle Julien, Reine El Omar, Manuela Tavian DOI: 10.1002/1873-3468.12389 http://onlinelibrary.wiley.com/doi/10.1002/1873-3468.12389/fullDionisio_{December 25, 2016
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