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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Pulsatile cell-autonomous contractility drives compaction in the mouse embryo Nature Cell Biology (2015) doi:10.1038/ncb3185 http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3185.html Mammalian embryos initiate morphogenesis with compaction, which is essential for specifying the first lineages of the blastocyst. The 8-cell-stage mouse embryo compacts by enlarging its cell–cell contacts in a Cdh1-dependent manner. Remarkably, contractions emerge as periodic cortical waves when cells are disengaged from adhesive contacts. In line with this, tension mapping of mzCdh1?/? embryos suggests that Cdh1 acts by redirecting contractility away from cell–cell contacts. Our study provides a framework to understand early mammalian embryogenesis [...]
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Condensin confers the longitudinal rigidity of chromosomes Nature Cell Biology 17, 771–781 (2015) doi:10.1038/ncb3167 http://www.nature.com/ncb/journal/v17/n6/full/ncb3167.html#t In addition to inter-chromatid cohesion, mitotic and meiotic chromatids must have three physical properties: compaction into ‘threads’ roughly co-linear with their DNA sequence, intra-chromatid cohesion determining their rigidity, and a mechanism to promote sister chromatid disentanglement. A fundamental issue in chromosome biology is whether a single molecular process accounts for all three features. There is universal agreement that a pair of Smc–kleisin complexes called condensin I and II facilitate sister chromatid disentanglement, but whether they also confer thread formation or longitudinal rigidity is either controversial or has never been directly addressed respectively. We show here that condensin II (beta-kleisin) has an essential role in all three processes during meiosis I in mouse oocytes and that its function overlaps with that of condensin I (gamma-kleisin), which is otherwise redundant. Pre-assembled meiotic bivalents unravel when condensin is inactivated by TEV cleavage, proving that it actually holds chromatin fibres together.
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The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signaling Nature Cell Biology (2015) doi:10.1038/ncb3179 http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3179.html The spindle assembly checkpoint (SAC) is a unique signalling mechanism that responds to the state of attachment of the kinetochore to spindle microtubules. SAC signalling is activated by unattached kinetochores, and it is silenced after these kinetochores form end-on microtubule attachments. Although the biochemical cascade of SAC signalling is well understood, how kinetochore–microtubule attachment disrupts it remained unknown. Here we show that, in budding yeast, end-on microtubule attachment to the kinetochore physically separates the Mps1 kinase, which probably binds to the calponin homology domain of Ndc80, from the kinetochore substrate of Mps1, Spc105 (KNL1 orthologue). This attachment-mediated separation disrupts the phosphorylation of Spc105, and enables SAC silencing. Additionally, the Dam1 complex may act as a barrier that shields Spc105 from Mps1. Together these data suggest that the protein architecture of the kinetochore encodes a mechanical switch. End-on microtubule attachment to the kinetochore turns this switch off to silence the SAC.
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Reconstitution of mitotic chromatids with a minimum set of purified factors Nature Cell Biology (2015) doi:10.1038/ncb3187 http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3187.html The assembly of mitotic chromosomes, each composed of a pair of rod-shaped chromatids, is an essential prerequisite for accurate transmission of the genome during cell division. It remains poorly understood, however, how this fundamental process might be achieved and regulated in the cell.
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#553 follow up Unexpected role? Why? Did they expect something else?Dionisio_{June 17, 2015
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A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint DOI: http://dx.doi.org/10.7554/eLife.05269 eLife 2015;4:e05269 http://elifesciences.org/content/4/e05269 [...] gene duplication and sub-functionalization shape the workings of an essential molecular network. The MCC, made of Cdc20/C-Mad2 and BubR1/Bub3, can be interpreted as a ‘copy’ of kinetochore-bound ‘templates’ made of Mad1/C-Mad2 and Bub1/Bub3 complexes. Whether such templates engage in a complex at kinetochores is unclear but plausible. [...] future studies will aim to investigate the significance of the copy–template molecular relationship for SAC signaling and chromosome bi-orientation. We surmise that BubR1-bound Bub3 is involved in an unknown aspect of the SAC mechanism downstream of kinetochores, [...] [...] we speculate that the BubR1 loop motif influences the specificity of BubR1-bound Bub3 for additional SAC-relevant targets.
"..., interpret, surmise, speculate, unclear but plausible,..." Outstanding questions answered, new questions raised. What else is new? Work in progress... stay tuned.Dionisio_{June 17, 2015
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DNA Damage Response and Spindle Assembly Checkpoint Function throughout the Cell Cycle to Ensure Genomic Integrity •DOI: 10.1371/journal.pgen.1005150 The role of the DDR in response to metaphase defects extends beyond CHK1 It is surprising that CHK-1 is phosphorylated in response to both monopolar spindle formation and following APC inactivation, yet is only required for the latter. MAD-1 and MAD-2 are required for maintaining chromosome and spindle stability once chromosomes have bi-oriented [...] the specific role of these phosphorylation events await future studies. http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005150
Work in progress... stay tuned.Dionisio_{June 17, 2015
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Kinetochore-localized BUB-1/BUB-3 complex promotes anaphase onset in C. elegant Kim et al. 209 (4): 507 JCB vol. 209 no. 4 507-517 The Rockefeller University Press, doi: 10.1083/jcb.201412035 The conserved Bub1/Bub3 complex is recruited to the kinetochore region of mitotic chromosomes, where it initiates spindle checkpoint signaling and promotes chromosome alignment. Here we show that, in contrast to the expectation for a checkpoint pathway component, the BUB-1/BUB-3 complex promotes timely anaphase onset in Caenorhabditis elegans embryos. This activity of BUB-1/BUB-3 was independent of spindle checkpoint signaling but required kinetochore localization. BUB-1/BUB-3 inhibition equivalently delayed separase activation and other events occurring during mitotic exit. The anaphase promotion function required BUB-1’s kinase domain, but not its kinase activity, and this function was independent of the role of BUB-1/BUB-3 in chromosome alignment. These results reveal an unexpected role for the BUB-1/BUB-3 complex in promoting anaphase onset that is distinct from its well-studied functions in checkpoint signaling and chromosome alignment, and suggest a new mechanism contributing to the coordination of the metaphase-to-anaphase transition. http://jcb.rupress.org/content/209/4/507.abstract
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MiCroKiTS 4.0: a database of midbody, centrosome, kinetochore, telomere and spindle Nucl. Acids Res. (2015) 43 (D1): D328-D334. doi: 10.1093/nar/gku1125 http://nar.oxfordjournals.org/content/43/D1/D328.full MiCroKiTS 4.0 (http://microkit.biocuckoo.org) for proteins temporally and spatially localized in distinct subcellular positions including midbody, centrosome, kinetochore, telomere and mitotic spindle during cell division/mitosis. [...] further experimental studies are still needed to verify the observations, while orthologs among distantly related species, such as organisms in different kingdoms, should be carefully considered.
Dionisio_{June 15, 2015
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An integrated overview of spatiotemporal organization and regulation in mitosis in terms of the proteins in the functional supercomplexes Front. Microbiol., http://dx.doi.org/10.3389/fmicb.2014.00573 Although the importance of organelles to cell biology has been repeatedly demonstrated by multiple reports over the past decades, many aspects of their function, structure and composition are still largely unknown. [...] there still remain a large number of proteins that are predicted to be associated with these organelles [...] a large number of proteins that are predicted to be located on the MTOC are still not well validated. Confirmation of the functions of these predicted proteins has broad implications for the understanding of the MTOC. [...] the molecular composition and the exact functions of the appendages remain largely unclear. The mechanisms underlying the assembly of the centriole are still poorly understood. [...] the precise components and regulators of ?-TuRCs remains incompletely understood. Up to now, only a portion of the centrosome components have been detected, and more efforts are required for the experimental validation of the remaining components. [...] there is still a large number of proteins located on the SPB that need to be further validated. [...] identification of the centrosomal proteins and clarification of the mechanisms underlying the centrosome assembly and regulation may lead to new drug targets, diagnostics or therapeutic approaches. [...] there are still a number of proteins localized at the kinetochore without any functional validation, as shown in the MiCroKiTS database. It is difficult to obtain the structural information on the complete kinetochore, so the structure is still not entirely clear. To further the understanding of the assembly process of the kinetochore and the mechanisms underlying chromosome segregation, additional kinetochore components and higher resolution images of kinetochore are needed to assist the elucidation of the structure and regulatory network. These are key elements in advancing our understanding of the mechanisms of the kinetochore-associated diseases, such as cancer, and may contribute to the development of early-stage clinical treatments. [...] more functions of the midbody are still unclear. [...] the current knowledge of the midbody components and the way the midbody proteins are organized is limited. [...] there are still many remaining components that urgently need to be uncovered and validated. [...] the detailed composition of midbody and bud neck is still not known. [...] identification of the midbody components is essential for advancing our knowledge of midbody and cell-fate determination, and also for exploring new therapeutic strategies for midbody related diseases treatment, such as cancer. Certainly, the current understanding of the mechanisms used by multi-localized proteins to dynamically control the formation and functions of subcellular structures is still limited. Future studies are needed to identify the components of the subcellular structures as well as the multi-localized proteins, and also to characterize their functions, on–off mechanisms and crosstalk. http://journal.frontiersin.org/article/10.3389/fmicb.2014.00573/full
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Two Polo-like kinase 4 binding domains in Asterless perform distinct roles in regulating kinase stability 2015 // JCB vol. 208 no. 4 401-414 The Rockefeller University Press, doi: 10.1083/jcb.201410105 http://jcb.rupress.org/content/208/4/401.abstract Plk4 (Polo-like kinase 4) and its binding partner Asterless (Asl) are essential*, conserved centriole assembly factors that induce** centriole amplification when overexpressed***. Previous studies found that Asl acts** as a scaffolding protein; its N terminus binds** Plk4’s tandem Polo box cassette (PB1-PB2) and targets** Plk4 to centrioles to initiate** centriole duplication. However, how Asl overexpression*** drives** centriole amplification is unknown. In this paper, we investigated the Asl–Plk4 interaction** in Drosophila melanogaster cells. Surprisingly****, the N-terminal region of Asl is not required for centriole duplication, but a previously unidentified Plk4-binding domain in the C terminus is required. Mechanistic analyses of the different Asl regions revealed that they act uniquely during the cell cycle**: the Asl N terminus promotes** Plk4 homodimerization and autophosphorylation during interphase, whereas the Asl C terminus stabilizes** Plk4 during mitosis. Therefore, Asl affects** Plk4 in multiple ways to regulate** centriole duplication. Asl not only targets** Plk4 to centrioles but also modulates** Plk4 stability and activity, explaining the ability of overexpressed*** Asl to drive** centriole amplification.
(*) is it sufficient too? (**) how? when? where? (***) how is that overexpression triggered? (****) why 'surprisingly'?Dionisio_{June 15, 2015
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Autoinhibition and relief mechanism for Polo-like kinase 4 PNAS vol. 112 no. 7 > Joseph E. Klebba, E657–E666, doi: 10.1073/pnas.1417967112 Polo-like kinases (Plks) are a conserved family of enzymes that function as master regulators for the process of cell division. Among their duties, Plks control the assembly of centrosomes, tiny organelles that facilitate mitotic spindle assembly and maintain the fidelity of chromosome inheritance. Plks are overexpressed in cancer, and therefore it is critical to unravel the normal regulation of these kinases. Unlike other Plks, Plk4 contains three rather than two Polo box domains, and the function of its third Polo box (PB3) is unclear. Like other Plks, Plk4 possesses a previously unidentified autoinhibitory mechanism mediated by a linker (L1) near the kinase domain. These findings reveal a complex mechanism of Plk4 regulation and activation which govern the process of centriole duplication. http://www.pnas.org/content/112/7/E657.abstract
Outstanding questions answered, newer questions raised. Work in progress… stay tuned.Dionisio_{June 15, 2015
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Condensin II Regulates Interphase Chromatin Organization Through the Mrg-Binding Motif of Cap-H2 Early Online 2015, doi: 10.1534/g3.115.016634 G3 May 1, 2015 vol. 5 no. 5 803-817 The spatial organization of the genome within the eukaryotic nucleus is a dynamic process that plays a central role in cellular processes such as gene expression, DNA replication, and chromosome segregation. [...] the mechanism by which Mrg15 and Cap-H2 cooperate to maintain interphase chromatin organization remains unclear. Determining whether Cap-H2 and Mrg15 function within the same multi-protein complex to coordinately regulate transcription of target genes and whether they do so in a cell type–specific or developmental stage–specific manner will provide valuable insight into the function of condensin complexes in maintenance of interphase genome organization and their contribution to proper control of gene expression. http://g3journal.org/content/5/5/803.full
Outstanding questions answered, newer questions raised. Work in progress... stay tuned.Dionisio_{June 15, 2015
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Plk4-dependent phosphorylation of STIL is required for centriole duplication doi: 10.1242/?bio.201411023 2015 Biology Open 4, 370-377. [...] we speculate that in particular phosphorylation on S1116 is involved in centrosome amplification. Interestingly, in previous studies phosphorylation of S1116 in STIL was also observed and shown to be important for centriole duplication. Future studies will be required to demonstrate how and when during the early cell cycle stages phosphorylation of STIL by Plk4 will initiate procentriole formation. http://bio.biologists.org/content/4/3/370.full
Outstanding questions answered, newer questions raised. What else is new?Dionisio_{June 15, 2015
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The E3 ubiquitin ligase Mib1 regulates Plk4 and centriole biogenesis doi: 10.1242/?jcs.166496 2015 J Cell Sci 128, 1674-1682. http://jcs.biologists.org/content/128/9/1674.abstract Centrioles function as core components of centrosomes and as basal bodies for the formation of cilia and flagella. Thus, effective control of centriole numbers is essential for embryogenesis, tissue homeostasis and genome stability. In mammalian cells, the centriole duplication cycle is governed by Polo?like kinase 4 (Plk4). Here, we identify the E3 ubiquitin ligase Mind bomb (Mib1) as a new interaction partner of Plk4. We show that Mib1 localizes to centriolar satellites but redistributes to centrioles in response to conditions that induce centriole amplification. The E3 ligase activity of Mib1 triggers ubiquitylation of Plk4 on multiple sites, causing the formation of Lys11?, Lys29? and Lys48?ubiquitin linkages. These modifications control the abundance of Plk4 and its ability to interact with centrosomal proteins, thus counteracting centriole amplification induced by excess Plk4. Collectively, these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis.
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Paternally contributed centrioles exhibit exceptional persistence Cell Research 25:642–644. doi:10.1038/cr.2015.49; http://www.nature.com/cr/journal/v25/n5/full/cr201549a.html The two gametes make different contributions to the zygote at fertilization. Although both gametes contribute genetic material, in most animal species the oocyte donates the bulk of cytoplasmic constituents and cellular organelles, including mitochondria, whereas the sperm donates two centrioles. How long the two centrioles contributed by the sperm persist in the developing embryo is not known in any system. [...] the extent to which their constituents persist over several cell cycles has been scarcely studied. [...] whether these and other centriolar components remain stable for more cell cycles is not known. [...] our data demonstrate that paternally contributed centriolar components exhibit remarkable persistence in the embryo. Our findings also raise the intriguing possibility that centrioles may act as information carriers across several cell cycles, for instance through posttranslational modifications of the persistent centriolar proteins reported here.
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Locomotion, Theta Oscillations, and the Speed-Correlated Firing of Hippocampal Neurons Are Controlled by a Medial Septal Glutamatergic Circuit Falko Fuhrmann, Daniel Justus, Liudmila Sosulina, Hiroshi Kaneko, Tatjana Beutel, Detlef Friedrichs, Susanne Schoch, Martin Karl Schwarz, Martin Fuhrmann, Stefan Remy DOI: http://dx.doi.org/10.1016/j.neuron.2015.05.001 Video presentation: https://www.youtube.com/embed/Q8BGehgXK94
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The RNA structurome: transcriptome-wide structure probing with next-generation sequencing doi:10.1016/j.tibs.2015.02.005 RNA folds into intricate structures that enable its pivotal roles in biology, ranging from regulation of gene expression to ligand sensing and enzymatic functions. Therefore, elucidating RNA structure can provide profound insights into living systems. An emerging view suggests potential links between RNA structure and stress and disease physiology across the tree of life. [...] these exciting findings open new frontiers into RNA biology, genome biology, and beyond. http://www.sciencedirect.com/science/article/pii/S0968000415000274
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NAD in RNA: unconventional headgear doi:10.1016/j.tibs.2015.03.004 Although widely assumed to bear a 5?-terminal triphosphate or monophosphate, recent evidence suggests that the 5? end of bacterial RNA can sometimes bear a modification reminiscent of a eukaryotic cap. A new study has now identified Escherichia coli RNAs that begin with a noncanonical cap resembling the redox cofactor nicotinamide adenine dinucleotide (NAD), as well as a cellular enzyme that can remove it. The biological function of such caps remains to be determined. http://www.sciencedirect.com/science/article/pii/S0968000415000420
Recent evidence from new studies raised new questions?Dionisio_{June 14, 2015
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Folding upon phosphorylation: translational regulation by a disorder-to-order transition doi:10.1016/j.tibs.2015.02.007 4E binding proteins (4E-BPs) play an important role in the regulation of translation by binding to eukaryotic translation initiation factor 4E (eIF4E) and inhibiting assembly of the eIF4F complex. While phosphorylation of 4E-BPs is known to disrupt their binding to eIF4E, the mechanism by which this occurs has been unclear. In a recent study, Forman-Kay and coworkers demonstrate that this mechanism is primarily structure-based: phosphorylation of 4E-BPs results in a disorder-to-order transition, bringing them from their binding-competent disordered state to a folded state incompatible with eIF4E binding. http://www.sciencedirect.com/science/article/pii/S0968000415000389
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#539 follow up
Integrator: surprisingly diverse functions in gene expression
surprisingly? Why? What else were they expecting?Dionisio_{June 14, 2015
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Integrator: surprisingly diverse functions in gene expression doi:10.1016/j.tibs.2015.03.005 The discovery of the metazoan-specific Integrator (INT) complex represented a breakthrough in our understanding of noncoding U-rich small nuclear RNA (UsnRNA) maturation and has triggered a reevaluation of their biosynthesis mechanism. In the decade since, significant progress has been made in understanding the details of its recruitment, specificity, and assembly. While some discrepancies remain on how it interacts with the C-terminal domain (CTD) of the RNA polymerase II (RNAPII) and the details of its recruitment to UsnRNA genes, preliminary models have emerged. Recent provocative studies now implicate INT in the regulation of protein-coding gene transcription initiation and RNAPII pause-release, thereby broadening the scope of INT functions in gene expression regulation. We discuss the implications of these findings while putting them into the context of what is understood about INT function at UsnRNA genes. http://www.sciencedirect.com/science/article/pii/S0968000415000432
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RNA–RNA interactions in gene regulation: the coding and noncoding players doi:10.1016/j.tibs.2015.03.001 The past few years have witnessed an exciting increase in the richness and complexity of RNA-mediated regulatory circuitries, including new types of RNA–RNA interaction that underlie key steps in gene expression control in an organized and probably hierarchic system to dictate final protein output. Both small (especially miRNAs) and long coding (lc) and noncoding (nc) RNAs contain structural domains that can sense and bind other RNAs via complementary base pairing. The versatility of the interaction confers multiple roles to RNA–RNA hybrids, from control of RNA biogenesis to competition for common targets. Here, we focus on the emerging evidence around RNA networks and their impact on gene expression regulation in light of recent breakthroughs around the crosstalk between coding RNAs and ncRNAs. http://www.sciencedirect.com/science/article/pii/S0968000415000390
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Non-coding RNA in control of gene regulatory programs in cardiac development and disease doi:10.1016/j.yjmcc.2015.03.014 http://www.sciencedirect.com/science/article/pii/S0022282815001005 Organogenesis of the vertebrate heart is a highly specialized process involving progressive specification and differentiation of distinct embryonic cardiac progenitor cell populations driven by specialized gene programming events. [...] these intricate genomic events are temporally and spatially regulated by complex signaling networks and gene regulatory networks. MicroRNAs regulate gene expression at the post-transcriptional level, and numerous studies have now established critical roles for this species of tiny RNAs in a broad range of aspects from cardiogenesis towards adult heart failure. Recent reports now also implicate the larger family of long non-coding RNAs (lncRNAs) in these processes as well.
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Non-coding RNAs: Epigenetic regulators of bone development and homeostasis http://www.sciencedirect.com/science/article/pii/S8756328215002070 doi:10.1016/j.bone.2015.05.026 Each class of ncRNAs operates through distinct mechanisms, but their pathways to regulating gene expression are interrelated in ways that are just being recognized. While the importance of lncRNAs in epigenetic control of transcription, developmental processes and human traits is emerging, the identity of lncRNAs in skeletal biology is scarcely known.
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Inhibition of Polo-like Kinase 1 (Plk1) Enhances the Anti-neoplastic Activity of Metformin in Prostate Cancer doi: 10.1074/jbc.M114.596817 http://www.jbc.org/content/early/2014/12/10/jbc.M114.596817 The widely used anti-diabetic drug metformin has been shown to exert strong anti-neoplastic actions in numerous tumor types, including prostate cancer. In this study, we show that BI2536?a specific Plk1 inhibitor, acts synergistically with metformin in inhibiting prostate cancer cell proliferation.
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Transcriptional control of mitosis: deregulation and cancer Somsubhra Nath, Dishari Ghatak, Pijush Das and Susanta Roychoudhury Front. Endocrinol., http://dx.doi.org/10.3389/fendo.2015.00060 The role of transcriptional regulatory pathways behind the incidence of tumorigenesis remains an enigma. [...] the list of transcripts whose transcription is affected by certain cell cycle or developmental transitions is being expanded owing to new genome-wide approaches. Answer to many open questions regarding the interplay between transcriptional regulation and mitotic progression will make an important contribution to the understanding of cell cycle control. http://journal.frontiersin.org/article/10.3389/fendo.2015.00060/full
Perhaps this post is related to the paper referenced @533?Dionisio_{June 14, 2015
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Mitotic Control of Planar Cell Polarity by Polo-like Kinase 1 Rezma Shrestha, Katherine A. Little, Joel V. Tamayo, Wenyang Li, David H. Perlman, Danelle Devenport DOI: http://dx.doi.org/10.1016/j.devcel.2015.03.024 During cell division, polarized epithelial cells employ mechanisms to preserve cell polarity and tissue integrity. The dramatic redistribution* of PCP proteins coincides precisely with cell-cycle progression, but the mechanisms coordinating PCP and mitosis are unknown. Plk1-mediated phosphorylation** of Celsr1 ensures that PCP redistribution is precisely coordinated with mitotic entry. http://www.cell.com/developmental-cell/abstract/S1534-5807(15)00220-8
(*) how is that dramatic redistribution done? (**) how is Plk1-mediated phosphorylation triggered?Dionisio_{June 14, 2015
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Mesenchymal condensation-dependent accumulation of collagen VI stabilizes organ-specific cell fates during embryonic tooth formation Developmental Dynamics Volume 244, Issue 6, pages 713–723 Tadanori Mammoto, Akiko Mammoto, Amanda Jiang, Elisabeth Jiang, Basma Hashmi and Donald E. Ingber DOI: 10.1002/dvdy.24264 the mechanism by which cell compaction is stabilized over time to ensure correct organ-specific cell fate switching remains unknown. the odontogenic differentiation process that is induced by cell compaction during mesenchymal condensation is stabilized and sustained through mechanically regulated production of collagen VI within the mesenchymal ECM. Developmental Dynamics, 2015. 244:713–723,
Dionisio_{June 13, 2015
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Lesson from the neuromuscular junction: role of pattern and timing of nerve activity in synaptic development DOI: 10.4103/1673-5374.156944 Favero M, Cangiano A, Busetto G. Lesson from the neuromuscular junction: role of pattern and timing of nerve activity in synaptic development. Neural Regen Res [serial online] 2015 [cited 2015 Jun 13];10:686-8. Available from: http://www.nrronline.org/text.asp?2015/10/5/686/156944 One important question is still unanswered: which are the molecular messengers involved in the competition/elimination process? Because of the instructive role of pattern of activity, in order to determine if a given molecule/cell mediates competition, its relation to the timing of activity must be investigated: for none of them this has yet been done. Unfortunately this proposed mechanism is based only on morphological observations, and no functional experiments have been performed to prove them. Moreover, its relationship to the timing of activity has not been explored. the neuromuscular junction, besides being the preparation were polyneuronal innervation and synapse elimination have been first described, is also one of primary election for the functional and mechanistic study of these phenomena and relevant for the understanding of the development of the entire brain. http://www.nrronline.org/article.asp?issn=1673-5374;year=2015;volume=10;issue=5;spage=686;epage=688;aulast=Favero
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8
08
42
AM
PDT}

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