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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The Notch signaling pathway orchestrates cell fate by either inducing cell differentiation or maintaining cells in an undifferentiated state. [...] the Notch1/survivin crosstalk contributes to the maintenance of stemness in human keratinocytes. Homeostasis of the adult epidermis is ensured by a delicate equilibrium of proliferation, differentiation, and apoptosis. Notch1 maintains stemness in human keratinocytes via a bi-directional cross-talk with survivin, independent of age. Because KSC are also responsible for tumor recurrences, targeting the Notch-survivin axis in these cells could result in strong anti-cancer activity.
Notch Cooperates with Survivin to Maintain Stemness and to Stimulate Proliferation in Human Keratinocytes during Ageing Elisabetta Palazzo 1,†, Paolo Morandi 1,†, Roberta Lotti 1, Annalisa Saltari 1, Francesca Truzzi 1, Sylvianne Schnebert 2, Marc Dumas 2, Alessandra Marconi 1 and Carlo Pincelli 1 Int. J. Mol. Sci. 2015, 16(11), 26291-26302; doi:10.3390/ijms161125948 http://www.mdpi.com/1422-0067/16/11/25948/htm

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Notch down-regulation in the epidermis appears to contribute to tissue regeneration during wound healing. . Notch was down-regulated in the regenerated epidermis during wound healing. •IL-36? expression was induced by Notch inhibition. •Notch down-regulation in the regenerated epidermis may reinforce defense against stress from the outside by inducing IL-36? expression. •Notch down-regulation suppressed induction of Keratin1/10 in keratinocytes. •The reduced levels of these keratins would increase cellular flexibility.
Notch down-regulation in regenerated epidermis contributes to enhanced expression of interleukin-36? and suppression of keratinocyte differentiation during wound healing Yuko Takazawa, Eisaku Ogawa, Rumiko Saito, Ryuhei Uchiyama, Shuntaro Ikawa, Hisashi Uhara, Ryuhei Okuyama DOI: http://dx.doi.org/10.1016/j.jdermsci.2015.04.003tggf http://www.jdsjournal.com/article/S0923-1811(15)00152-8/abstract

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Focused investigations that concentrate on the time course will reveal much about both the impact and mechanisms of epigenetic phenomena.
Dynamics of epigenetic phenomena: intergenerational and intragenerational phenotype ‘washout’ Warren W. Burggren Journal of Experimental Biology 2015 218: 80-87; doi: 10.1242/jeb.107318 http://jeb.biologists.org/content/218/1/80.abstract#abstract-1

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Our former “certainties” about DNA’s function and its role in inheritance—such as the non-functional nature of non-protein coding (junk) DNA, and the sole role of genes in inheritance—have been eroded over the years by discovery after discovery that overturns previous assumptions and adds new layers of complexity. That gene function can be regulated across generations though epigenetic mechanisms is very likely just the latest chapter in a large and detailed book on inheritance that remains to be completed.
Epigenetics in Comparative Biology: Why We Should Pay Attention Warren W. Burggren1,* and David Crews† Integr. Comp. Biol. 54 (1): 7-20. doi: 10.1093/icb/icu013 http://icb.oxfordjournals.org/content/54/1/7.full

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The literature on epigenetics is growing at an almost unprecedented rate, and the full reach of epigenetics in the intra-generational and transgenerational manifestations of human disease is only beginning to be exposed. Additionally, epigenetics is emerging not just as a pathway for disease, but also as a highly reactive mechanism for short-term adaptation to changing environmental conditions, and as such is likely to be a key ingredient in the deeper understanding of gene–environment interactions in environmental biology.
Epigenetics in Comparative Biology: Why We Should Pay Attention Warren W. Burggren1,* and David Crews† Integr. Comp. Biol. 54 (1): 7-20. doi: 10.1093/icb/icu013 http://icb.oxfordjournals.org/content/54/1/7.full

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Epigenetics is an exciting, yet still somewhat enigmatic and highly immature, field of biology.
Epigenetics in Comparative Biology: Why We Should Pay Attention Warren W. Burggren1,* and David Crews† Integr. Comp. Biol. 54 (1): 7-20. doi: 10.1093/icb/icu013 http://icb.oxfordjournals.org/content/54/1/7.full

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[...] the timing of production and integration of each of the neuronal subtypes must be coordinated on a species-specific developmental time scale. Growing evidence now demonstrates that the transitions between sequential layer subtypes utilize a regulatory system that integrates both intrinsic and extrinsic mechanisms. [...] hierarchical transcriptional and intercellular network organization promotes the cost-effective production and wiring of neurons during development [...] Continuous efforts to decipher the molecular mechanisms of subtype-specific neuronal differentiation and their integration, would facilitate our understanding of the logic that balance between economical brain assembly and vulnerability to pathological conditions.
Switching modes in corticogenesis: mechanisms of neuronal subtype transitions and integration in the cerebral cortex Kenichi Toma and Carina Hanashima Front. Neurosci., http://dx.doi.org/10.3389/fnins.2015.00274 http://journal.frontiersin.org/article/10.3389/fnins.2015.00274/full

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Information processing in the cerebral cortex requires the activation of diverse neurons across layers and columns, which are established through the coordinated production of distinct neuronal subtypes and their placement along the three-dimensional axis. Neocortical assembly is a highly intricate process that requires multiple layers of regulation in cell behavior at the progenitor and postmitotic cell stages. The emerging picture of neocortical assembly is that while the identities of neuronal subtypes are largely determined at birth, the mechanisms by which these neurons are navigated to their final positions involve cell type- and context-dependent combinatorial codes that enable their precise integration into the neocortical circuit. [...] the molecular logic underlying these subtype transitions has only begun to unravel over the past years.
Switching modes in corticogenesis: mechanisms of neuronal subtype transitions and integration in the cerebral cortex Kenichi Toma and Carina Hanashima Front. Neurosci., http://dx.doi.org/10.3389/fnins.2015.00274 http://journal.frontiersin.org/article/10.3389/fnins.2015.00274/full

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Neocortical development requires tightly controlled spatiotemporal gene expression. However, the mechanisms regulating ribosomal complexes and the timed specificity of neocortical mRNA translation are poorly understood.
Thalamic WNT3 Secretion Spatiotemporally Regulates the Neocortical Ribosome Signature and mRNA Translation to Specify Neocortical Cell Subtypes Matthew L. Kraushar, Barbara Viljetic, H. R. Sagara Wijeratne, Kevin Thompson, Xinfu Jiao, Jack W. Pike, Vera Medvedeva, Matthias Groszer, Megerditch Kiledjian, Ronald P. Hart, and Mladen-Roko Rasin The Journal of Neuroscience, 35(31): 10911-10926; doi: 10.1523/JNEUROSCI.0601-15.2015 http://www.jneurosci.org/content/35/31/10911.abstract?etoc

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Identifying RNA targets for RBPs is critical to gain a mechanistic understanding of how these RBPs help shape the developing brain. Future studies which couple optimized RNA immunoprecipitation approaches with single cell resolution will be ideal. The future is exciting for RNA regulation in corticogenesis as the advent of new technologies will lead to great advances in this field of research.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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[...] we have just scratched the surface in terms of a comprehensive understanding of how RBPs influence cortical development and which RBPs are important. [...] virtually all aspects of posttranscriptional regulation are implicated in corticogenesis. Many fundamental questions now remain to be answered. How is RNA regulation coordinated within rapidly dividing populations across stages of embryonic development? What additional RBPs influence corticogenesis, how do they do so, and what are their key targets? What role does RNA stability play in modulating cell fate choices in the developing brain? Answering these questions in a complex tissue such as the embryonic mammalian cortex is challenging and will require multidisciplinary approaches encompassing bioinformatics, biochemistry, and genetics.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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With identification of Msi translational targets, it will be of interest in upcoming studies to assess the role of these Msi targets upon NSC behavior in the cortex. Future work is needed to identify those potential targets, and to assess their contribution to behavior of NSCs and neurons. [...] it will be exciting in the future to test this model. It will also be valuable to demonstrate the direct role of Eif4E1/4E-T on translation of key mRNAs in NSCs, [...] Identification of the transmachinery, including RBPs that bind CyclinD2 will be useful for understanding why it is asymmetrically localized in NSCs, and for identifying additional localized RNAs. Future studies and identification of asymmetrically localized mRNAs and RBPs in mitotic neural progenitors will help define whether this mechanism is broadly used for cell fate determination in the mammalian cortex.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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Outside of the nucleus, RNA stability and translational regulation offer yet another layer of control for gene expression. The role for RNA stability in corticogenesis is poorly defined. [...] regulated by the coordination between ribosomal complexes and a vast set of RBPs. [...] HuR regulates the position, identity and maturation of post-mitotic glutamatergic neurons. Future work will be valuable to further identify the molecular mechanisms by which HuR regulates these developmental processes. [...] this study sets the stage for future identification of signals that influence temporal control of mRNA translation.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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As splicing proceeds, spliced transcripts become decorated by exon junction complexes (EJC), which bind primarily at the junctions where introns are excised. The EJC remains bound to the spliced mRNA as the RNA is exported into the cytoplasm. Future studies will be useful to assess how Magoh impacts radial glia divisions either via translation and/or some other step in mRNA metabolism. Future genetic and molecular studies of these mutants will help establish which aspect(s) of EJC regulation are critical to development of the brain.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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In the future it will be of interest to identify additional splicing targets genome-wide that may also be regulated by Nova2 in the developing cerebral cortex. [...] RNA-targets of PTBP2 involved in the regulation of neurogenesis have not yet been identified [...] [...] AS regulation plays a critical role in cortical development. Given the abundance of splicing factors in the developing brain, clearly these studies are just the tip of the iceberg.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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[...] in addition to spatial differences in AS, temporal differences in AS are evident across different stages of cortical development. [...] AS is at play in the developing cerebral cortex across multiple dimensions (tangential, radial, and temporal). Future studies that similarly apply cell sorting and/or single cell transcriptome analysis will be valuable for further discovery of AS differences in cortical development. The spatio-temporal regulation of AS relies on the differential expression and function of trans-splicing factors including RBPs.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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Alternative splicing (AS) is a powerful mechanism to amplify the output diversity of the genome through the editing of primary transcripts. The excision or inclusion of intronic and exonic sequences of pre-mRNA produces distinct transcripts that may be translated into biochemically diverse proteins. As embryonic development proceeds, the repertoire of progenitors and neurons also changes.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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The cerebral cortex is the most complex biological “machine” known to man. Part of this complexity resides in the web of coordinated functional units, the cortical areas. During embryonic development, excitatory neurons are generated from neural progenitor populations in a process termed neurogenesis. [...] the fate and final function of projection neurons is ultimately defined by their birth and subsequent migration to distinct layers of the brain.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post-transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research.
Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain Louis-Jan Pilaz and Debra L. Silver DOI: 10.1002/wrna.1289 Wiley Interdisciplinary Reviews: RNA Volume 6, Issue 5, pages 501–515 http://onlinelibrary.wiley.com/doi/10.1002/wrna.1289/abstract

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Cell biologists now have tools and knowledge to generate useful quantitative data. But how can we make sense of these data, and are we measuring the correct parameters? The study of complex biological systems requires a strong effort to give a detailed description of the components and of their interactions. [...] do we really understand how the cell machinery works? Have we mastered the essential properties and control parameters to a point that would allow us to tune the cell system in a way that we determine? [...] cell biologists value and have mastered a reductionist approach: the cell is such a complex system that understanding can only emerge from breaking its mechanisms into subparts and describing each of them in detail. As it can unify different fields of life sciences, and compare accurately and quickly between various biological systems, theory is an exceptional motor to discover general properties of biological systems. The future of life sciences in general, and of cell biology in particular, is quantitative. Only a quantitative understanding allows us to accurately test hypothesis.
When cell biology meets theory Marcos Gonzalez-Gaitan and Aurélien Roux JCB vol. 210 no. 7 1041-1045 The Rockefeller University Press, doi: 10.1083/jcb.201504025 http://intl-jcb.rupress.org/content/210/7/1041.full

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Duplication of the yeast centrosome (called the spindle pole body, SPB) is thought to occur through a series of discrete steps that culminate in insertion of the new SPB into the nuclear envelope (NE). Our observation that proteins involved in membrane insertion, such as Mps2, Bbp1, and Ndc1, also accumulate at the new SPB early in duplication suggests that SPB assembly and NE insertion are coupled events during SPB formation in wild-type cells.
Structured illumination with particle averaging reveals novel roles for yeast centrosome components during duplication Shannon Burns, Jennifer S Avena, Jay R Unruh, Zulin Yu, Sarah E Smith, Brian D Slaughter, Mark Winey, Sue L Jaspersen DOI: http://dx.doi.org/10.7554/eLife.08586 SeLife 2015;4:e08586

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It will be of great interest to determine whether centrin phosphorylation by CDKs or alternative kinases can modulate the assembly of arrays of Sfi1 orthologs to control their functions in centrosomes in other eukaryotes.
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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[...] other regulatory mechanisms might function in parallel to Cdc31 phosphorylation to promote bridge splitting and release the two duplicated SPBs. In any case, this precludes drawing conclusions on the possible role of this consensus Cdk1 site in controlling SPB separation.
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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An alternative role for the phosphorylation of fission yeast Cdc31 N?terminus is to modulate the oligomerization of Sfi1–Cdc31 complexes in parallel arrays. Additional biochemical work might solve this question if fission yeast Sfi1 can be purified in a soluble form It is therefore possible that interactions between Sfi1–Cdc31 complexes involve additional interactions and regulations [...]
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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New tools will be necessary to establish the precise pattern of phosphorylation of serine 15 according to cell cycle progression. Another point that remains to be elucidated is the exact effect of serine 15 phosphorylation on Sfi1–Cdc31 arrays.
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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Whether an SPB precursor or satellite assembles immediately upon half?bridge duplication remains to be determined.
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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The mitotic spindle is a complex microtubule?based structure responsible for the accurate segregation of chromosomes. Its assembly and function are therefore under strict and robust regulatory mechanisms. [...] the Cdc31 N?terminus modulates the stability of Sfi1–Cdc31 arrays in fission yeast, and impacts on the timing of establishment of spindle bipolarity.
Cell cycle control of spindle pole body duplication and splitting by Sfi1 and Cdc31 in fission yeast Imène B. Bouhlel, Midori Ohta, Adeline Mayeux, Nicole Bordes, Florent Dingli, Jérôme Boulanger, Guilhem Velve Casquillas, Damarys Loew, Phong T. Tran, Masamitsu Sato, Anne Paoletti J Cell Sci 128: 1481-1493; doi: 10.1242/jcs.159657 http://jcs.biologists.org/content/128/8/1481.full

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A more complete understanding of the regulation of tissue morphodynamics will require better linking of molecular signaling to current mechanical models that describe changes in tissue shape based on localized contractility.
Regulation of tissue morphodynamics: an important role for actomyosin contractility Michael J Siedlik, Celeste M Nelson Current Opinion in Genetics & Development Volume 32, Pages 80–85 Developmental mechanisms, patterning and organogenesis doi:10.1016/j.gde.2015.01.002 http://www.sciencedirect.com/science/article/pii/S0959437X15000039

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[...] precisely how effectors of PCP lead to polarized myosin II activity or local actin remodeling remains an area of intense interest.
Tissue patterning and cellular mechanics Evan Heller and Elaine Fuchs doi: 10.1083/jcb.201506106 JCB vol. 211 no. 2 219-231 http://intl-jcb.rupress.org/content/211/2/219.full

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How the PCP pathway regulates contractility, adhesion, and local actin dynamics to achieve different ends in tissue patterning remains a fascinating but unresolved question.
Tissue patterning and cellular mechanics Evan Heller and Elaine Fuchs doi: 10.1083/jcb.201506106 JCB vol. 211 no. 2 219-231 http://intl-jcb.rupress.org/content/211/2/219.full

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