The Experts below are selected from a list of 20268 Experts worldwide ranked by ideXlab platform
William S Talbot - One of the best experts on this subject based on the ideXlab platform.
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Myelination induces axonal hotspots of synaptic vesicle fusion that promote sheath growth
Current Biology, 2021Co-Authors: Rafael G Almeida, William S Talbot, Jill M Williamson, Megan E Madden, Jason J Early, Matthew G Voas, Isaac H. Bianco, David A LyonsAbstract:Summary Myelination of axons by oligodendrocytes enables fast saltatory conduction. Oligodendrocytes are responsive to neuronal activity, which has been shown to induce changes to myelin sheaths, potentially to optimize conduction and neural circuit function. However, the cellular bases of activity-regulated Myelination in vivo are unclear, partly due to the difficulty of analyzing individual myelinated axons over time. Activity-regulated Myelination occurs in specific neuronal subtypes and can be mediated by synaptic vesicle fusion, but several questions remain: it is unclear whether vesicular fusion occurs stochastically along axons or in discrete hotspots during Myelination and whether vesicular fusion regulates myelin targeting, formation, and/or growth. It is also unclear why some neurons, but not others, exhibit activity-regulated Myelination. Here, we imaged synaptic vesicle fusion in individual neurons in living zebrafish and documented robust vesicular fusion along axons during Myelination. Surprisingly, we found that axonal vesicular fusion increased upon and required Myelination. We found that axonal vesicular fusion was enriched in hotspots, namely the heminodal non-myelinated domains into which sheaths grew. Blocking vesicular fusion reduced the stable formation and growth of myelin sheaths, and chemogenetically stimulating neuronal activity promoted sheath growth. Finally, we observed high levels of axonal vesicular fusion only in neuronal subtypes that exhibit activity-regulated Myelination. Our results identify a novel “feedforward” mechanism whereby the process of Myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, consolidates sheath growth along specific axons selected for Myelination.
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Synaptic vesicle fusion along axons is driven by Myelination and subsequently accelerates sheath growth in an activity-regulated manner
2020Co-Authors: Jill M Williamson, William S Talbot, Megan E Madden, Jason J Early, Matthew G Voas, Isaac H. BiancoAbstract:To study activity-regulated Myelination, we imaged synaptic vesicle fusion along single axons in living zebrafish, and found, surprisingly, that axonal synaptic vesicle fusion is driven by Myelination. This myelin-induced axonal vesicle fusion was enriched along the unmyelinated domains into which newly-formed sheaths grew, and was promoted by neuronal activity, which in turn accelerated sheath growth. Our results indicate that neuronal activity consolidates sheath growth along axons already selected for Myelination.
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the lysosomal transcription factor tfeb represses Myelination downstream of the rag ragulator complex
Developmental Cell, 2018Co-Authors: Angela M A Meireles, Kimberle Shen, Lida Zoupi, Harini Iyer, Ellen L Bouchard, Anna Williams, William S TalbotAbstract:Summary Myelin allows for fast and efficient axonal conduction, but much remains to be determined about the mechanisms that regulate myelin formation. To investigate the genetic basis of Myelination, we carried out a genetic screen using zebrafish. Here, we show that the lysosomal G protein RagA is essential for CNS Myelination. In rraga−/− mutant oligodendrocytes, target genes of the lysosomal transcription factor Tfeb are upregulated, consistent with previous evidence that RagA represses Tfeb activity. Loss of Tfeb function is sufficient to restore Myelination in RagA mutants, indicating that hyperactive Tfeb represses Myelination. Conversely, tfeb−/− single mutants exhibit ectopic myelin, further indicating that Tfeb represses Myelination during development. In a mouse model of de- and reMyelination, TFEB expression is increased in oligodendrocytes, but the protein is localized to the cytoplasm, and hence inactive, especially during reMyelination. These results define essential regulators of Myelination and may advance approaches to therapeutic reMyelination.
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individual neuronal subtypes exhibit diversity in cns Myelination mediated by synaptic vesicle release
Current Biology, 2016Co-Authors: Sigrid Koudelka, William S Talbot, Matthew G Voas, Marion Baraban, Rafael G Almeida, Jan Soetaert, Martin P Meyer, David A LyonsAbstract:Regulation of Myelination by oligodendrocytes in the CNS has important consequences for higher-order nervous system function (e.g., [1-4]), and there is growing consensus that neuronal activity regulates CNS Myelination (e.g., [5-9]) through local axon-oligodendrocyte synaptic-vesicle-release-mediated signaling [10-12]. Recent analyses have indicated that Myelination along axons of distinct neuronal subtypes can differ [13, 14], but it is not known whether regulation of Myelination by activity is common to all neuronal subtypes or only some. This limits insight into how specific neurons regulate their own conduction. Here, we use a novel fluorescent fusion protein reporter to study Myelination along the axons of distinct neuronal subtypes over time in zebrafish. We find that the axons of reticulospinal and commissural primary ascending (CoPA) neurons are among the first myelinated in the zebrafish CNS. To investigate how activity regulates Myelination by different neuronal subtypes, we express tetanus toxin (TeNT) in individual reticulospinal or CoPA neurons to prevent synaptic vesicle release. We find that the axons of individual tetanus toxin expressing reticulospinal neurons have fewer myelin sheaths than controls and that their myelin sheaths are 50% shorter than controls. In stark contrast, Myelination along tetanus-toxin-expressing CoPA neuron axons is entirely normal. These results indicate that while some neuronal subtypes modulate Myelination by synaptic vesicle release to a striking degree in vivo, others do not. These data have implications for our understanding of how different neurons regulate Myelination and thus their own function within specific neuronal circuits.
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a g protein coupled receptor is essential for schwann cells to initiate Myelination
Science, 2009Co-Authors: Kelly R Monk, Stephen G Naylor, Thomas D Glenn, Sara Mercurio, Julie R Perlin, Claudia X Dominguez, Cecilia B Moens, William S TalbotAbstract:The myelin sheath allows axons to conduct action potentials rapidly in the vertebrate nervous system. Axonal signals activate expression of specific transcription factors, including Oct6 and Krox20, that initiate Myelination in Schwann cells. Elevation of cyclic adenosine monophosphate (cAMP) can mimic axonal contact in vitro, but the mechanisms that regulate cAMP levels in vivo are unknown. Using mutational analysis in zebrafish, we found that the G protein-coupled receptor Gpr126 is required autonomously in Schwann cells for Myelination. In gpr126 mutants, Schwann cells failed to express oct6 and krox20 and were arrested at the promyelinating stage. Elevation of cAMP in gpr126 mutants, but not krox20 mutants, could restore Myelination. We propose that Gpr126 drives the differentiation of promyelinating Schwann cells by elevating cAMP levels, thereby triggering Oct6 expression and Myelination.
Jonah R Chan - One of the best experts on this subject based on the ideXlab platform.
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phosphorylation of cytohesin 1 by fyn is required for initiation of Myelination and the extent of Myelination during development
Science Signaling, 2012Co-Authors: Junji Yamauchi, Jonah R Chan, Tomohiro Torii, Yuki Miyamoto, Shou Takashima, Kazumi Kondo, Katsumasa Kawahara, Noriko Nemoto, Gozoh Tsujimoto, Akito TanoueAbstract:Schwann cells respond to cues from axons by transforming their cellular morphology and forming myelin. We demonstrated that the guanine nucleotide exchange factor (GEF) cytohesin-1 promoted Myelination by activating the small guanosine triphosphatase (GTPase) Arf6. In mice, ablating cytohesin-1 delayed Myelination and diminished the amount of myelin produced. We determined that the Src-family kinase Fyn phosphorylated tyrosine 382 (Y 382 ) of cytohesin-1, and we generated transgenic mice that expressed a Schwann cell–specific phosphorylation mutant of cytohesin-1 (Y382F) that could not be targeted by Fyn. During development, these transgenic mice displayed delayed Myelination compared to that of wild-type mice, as well as a decrease in the amount of myelin produced, similar to that observed in cytohesin-1 −/− mice. These findings demonstrate that phosphorylation of cytohesin-1 by Fyn is required for full Myelination and suggest that tyrosine phosphorylation of GEFs may be a mechanism to activate small GTPases engaged in cell morphogenesis.
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A culture system to study oligodendrocyte Myelination processes using engineered nanofibers
Nature Methods, 2012Co-Authors: Michelle K Leach, S Y Christin Chong, Samuel J Tuck, Joseph M Corey, Stephanie A Redmond, Synthia H Mellon, Zhang-qi Feng, Jonah R ChanAbstract:Current methods for studying central nervous system Myelination necessitate permissive axonal substrates conducive to myelin wrapping by oligodendrocytes. We have developed a neuron-free culture system in which electron-spun nanofibers of varying sizes substitute for axons as a substrate for oligodendrocyte Myelination, thereby allowing manipulation of the biophysical elements of axonal-oligodendroglial interactions. To investigate axonal regulation of Myelination, this system effectively uncouples the role of molecular (inductive) cues from that of biophysical properties of the axon. We use this method to uncover the causation and sufficiency of fiber diameter in the initiation of concentric wrapping by rat oligodendrocytes. We also show that oligodendrocyte precursor cells display sensitivity to the biophysical properties of fiber diameter and initiate membrane ensheathment before differentiation. The use of nanofiber scaffolds will enable screening for potential therapeutic agents that promote oligodendrocyte differentiation and Myelination and will also provide valuable insight into the processes involved in reMyelination. Primary rat oligodendocytes were cultured in the presence of electron-spun nanofibers of varying sizes as a model to study Myelination processes in the mammalian central nervous system. The authors study the role of fiber diameter on the initiation of concentric wrapping by oligodendrocytes.
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anterograde transport and secretion of brain derived neurotrophic factor along sensory axons promote schwann cell Myelination
The Journal of Neuroscience, 2007Co-Authors: Lian Chen, Jose Miguel Cosgaya, Wilhelm Mandemakers, Jonah R ChanAbstract:The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits Schwann cell (SC) migration and promotes Myelination via the p75 neurotrophin receptor (NTR). Despite these recent findings, the expression, localization, and mechanism of BDNF action has yet to be determined. Here we demonstrate that the sensory neurons of the dorsal root ganglion (DRG) are a major source of BDNF during postnatal development. The expression of BDNF is initially elevated before Myelination and decreases dramatically after the onset of Myelination. BDNF expression is controlled in part by transcriptional regulation and the increased expression of the truncated TrkB receptor on SCs. To investigate the possible mechanism of BDNF transport and release, multicompartment Campenot chambers were used. DRG neurons transported and secreted endogenous BDNF along the surface of axons in anterograde fashion. In an attempt to enhance Myelination by SCs, DRG neurons were transduced with an adenovirus to overexpress BDNF. BDNF was transported and secreted along the axons and enhanced Myelination when compared with control cocultures. Together, the events surrounding the expression, localization, and mechanism of BDNF action in DRG neurons may hint at potential therapeutic implications to efficiently promote reMyelination.
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ngf controls axonal receptivity to Myelination by schwann cells or oligodendrocytes
Neuron, 2004Co-Authors: Jonah R Chan, Trent A Watkins, Jose Miguel Cosgaya, Chunzhao Zhang, Lian Chen, Louis F Reichardt, Eric M Shooter, Ben A BarresAbstract:Axons dictate whether or not they will become myelinated in both the central and peripheral nervous systems by providing signals that direct the development of myelinating glia. Here we identify the neurotrophin nerve growth factor (NGF) as a potent regulator of the axonal signals that control Myelination of TrkA-expressing dorsal root ganglion neurons (DRGs). Unexpectedly, these NGF-regulated axonal signals have opposite effects on peripheral and central Myelination, promoting Myelination by Schwann cells but reducing Myelination by oligodendrocytes. These findings indicate a novel role for growth factors in regulating the receptivity of axons to Myelination and reveal that different axonal signals control central and peripheral Myelination.
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neurotrophins are key mediators of the Myelination program in the peripheral nervous system
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Jonah R Chan, Jose Miguel Cosgaya, Eric M ShooterAbstract:Although knowledge of the functions of neurotrophins has advanced rapidly in recent years, studies concerning the involvement of neurotrophins in glial-neuronal interactions rarely extend further than their roles in supporting the survival and differentiation of neuronal cells. In this study endogenous brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) were identified in Schwann cell/dorsal root ganglia neuronal cocultures and shown to modulate the Myelination program of the peripheral nervous system. The differential expression of BDNF and NT3 were examined and compared with the expression profiles of myelin proteins in the cocultures throughout the Myelination process. BDNF levels correlated with active myelin formation, whereas NT3 expression was initially high and then down regulated throughout the proliferation and preMyelination periods. Addition of exogenous BDNF enhanced Myelination, whereas the removal of the endogenous BDNF by using the BDNF receptor TrkB-Fc fusion protein inhibited the formation of mature myelin internodes. Interestingly, exogenous NT3 significantly inhibited Myelination, whereas the removal of the endogenous NT3 by using the NT3 receptor TrkC-Fc fusion protein resulted in an enhancement similar to that obtained with the addition of BDNF. In addition, in vivo studies were performed during the development of the mouse sciatic nerve. Subcutaneous injections of BDNF resulted in an enhancement of myelin formation in the sciatic nerve, whereas the removal of the endogenous BDNF dramatically inhibited Myelination. Injections of NT3 inhibited myelin formation, and the removal of the endogenous NT3 enhanced Myelination. These results demonstrate that BDNF and NT3 possess different modulatory roles in the Myelination program of the peripheral nervous system and that their mechanisms of action are specific and highly regulated.
James L. Salzer - One of the best experts on this subject based on the ideXlab platform.
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akt regulates axon wrapping and myelin sheath thickness in the pns
The Journal of Neuroscience, 2016Co-Authors: Roman Chrast, Enric Domenechestevez, Hasna Baloui, Xiaosong Meng, Yanqing Zhang, Katrin Deinhardt, Jeff Dupree, Steven Einheber, James L. SalzerAbstract:The signaling pathways that regulate Myelination in the PNS remain poorly understood. Phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, activated in Schwann cells by neuregulin and the extracellular matrix, has an essential role in the early events of Myelination. Akt/PKB, a key effector of phosphatidylinositol-4,5-bisphosphate 3-kinase 1A, was previously implicated in CNS, but not PNS Myelination. Here we demonstrate that Akt plays a crucial role in axon ensheathment and in the regulation of myelin sheath thickness in the PNS. Pharmacological inhibition of Akt in DRG neuron-Schwann cell cocultures dramatically decreased MBP and P0 levels and myelin sheath formation without affecting expression of Krox20/Egr2, a key transcriptional regulator of Myelination. Conversely, expression of an activated form of Akt in purified Schwann cells increased expression of myelin proteins, but not Krox20/Egr2, and the levels of activated Rac1. Transgenic mice expressing a membrane-targeted, activated form of Akt under control of the 2′,3′-cyclic nucleotide 3′-phosphodiesterase promoter, exhibited thicker PNS and CNS myelin sheaths, and PNS myelin abnormalities, such as tomacula and myelin infoldings/outfoldings, centered around the paranodes and Schmidt Lanterman incisures. These effects were corrected by rapamycin treatment in vivo . Importantly, Akt activity in the transgenic mice did not induce Myelination of nonmyelinating Schwann cells in the sympathetic trunk or Remak fibers of the dorsal roots, although, in those structures, they wrapped membranes redundantly around axons. Together, our data indicate that Akt is crucial for PNS Myelination driving axonal wrapping by unmyelinated and myelinated Schwann cells and enhancing myelin protein synthesis in myelinating Schwann cells. SIGNIFICANCE STATEMENT Although the role of the key serine/threonine kinase Akt in promoting CNS Myelination has been demonstrated, its role in the PNS has not been established and remains uncertain. This work reveals that Akt controls several key steps of the PNS Myelination. First, its activity promotes membrane production and axonal wrapping independent of a transcriptional effect. In myelinated axons, it also enhances myelin thickness through the mTOR pathway. Finally, sustained Akt activation in Schwann cells leads to hyperMyelination/dysMyelination, mimicking some features present in neuropathies, such as hereditary neuropathy with liability to pressure palsies or demyelinating forms of Charcot-Marie-Tooth disease. Together, these data demonstrate the role of Akt in regulatory mechanisms underlying axonal wrapping and Myelination in the PNS.
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soluble neuregulin 1 has bifunctional concentration dependent effects on schwann cell Myelination
The Journal of Neuroscience, 2010Co-Authors: Neeraja Syed, James L. Salzer, David P. Yang, Patrice Maurel, Carla Taveggia, Kavya Reddy, Haesun A KimAbstract:Members of the neuregulin-1 (Nrg1) growth factor family play important roles during Schwann cell development. Recently, it has been shown that the membrane-bound type III isoform is required for Schwann cell Myelination. Interestingly, however, Nrg1 type II, a soluble isoform, inhibits the process. The mechanisms underlying these isoform-specific effects are unknown. It is possible that Myelination requires juxtacrine Nrg1 signaling provided by the membrane-bound isoform, whereas paracrine stimulation by soluble Nrg1 inhibits the process. To investigate this, we asked whether Nrg1 type III provided in a paracrine manner would promote or inhibit Myelination. We found that soluble Nrg1 type III enhanced Myelination in Schwann cell-neuron cocultures. It improved Myelination of Nrg1 type III +/− neurons and induced Myelination on normally nonmyelinated sympathetic neurons. However, soluble Nrg1 type III failed to induce Myelination on Nrg1 type III −/− neurons. To our surprise, low concentrations of Nrg1 type II also elicited a similar promyelinating effect. At high doses, however, both type II and III isoforms inhibited Myelination and increased c-Jun expression in a manner dependent on Mek/Erk (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) activation. These results indicate that paracrine Nrg1 signaling provides concentration-dependent bifunctional effects on Schwann cell Myelination. Furthermore, our studies suggest that there may be two distinct steps in Schwann cell Myelination: an initial phase dependent on juxtacrine Nrg1 signaling and a later phase that can be promoted by paracrine stimulation.
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type iii neuregulin 1 promotes oligodendrocyte Myelination
Glia, 2008Co-Authors: Carla Taveggia, Ashley Petrylak, Steven Einheber, Pratik Thaker, Gregg L Caporaso, Arrel D Toews, Douglas L Falls, James L. SalzerAbstract:The axonal signals that regulate oligodendrocyte Myelination during development of the central nervous system (CNS) have not been established. In this study, we have examined the regulation of oligodendrocyte Myelination by the type III isoform of neuregulin-1 (NRG1), a neuronal signal essential for Schwann cell differentiation and Myelination. In contrast to Schwann cells, primary oligodendrocytes differentiate normally when cocultured with dorsal root ganglia (DRG) neurons deficient in type III NRG1. However, they myelinate type III NRG1-deficient neurites poorly in comparison to wild type cultures. Type III NRG1 is not sufficient to drive oligodendrocyte Myelination as sympathetic neurons are not myelinated even with lentiviral-mediated expression of NRG1. Mice haploinsufficient for type III NRG1 are hypomyelinated in the brain, as evidenced by reduced amounts of myelin proteins and lipids and thinner myelin sheaths. In contrast, the optic nerve and spinal cord of heterozygotes are myelinated normally. Together, these results implicate type III NRG1 as a significant determinant of the extent of Myelination in the brain and demonstrate important regional differences in the control of CNS Myelination. They also indicate that oligodendrocyte Myelination, but not differentiation, is promoted by axonal NRG1, underscoring important differences in the control of Myelination in the CNS and peripheral nervous system (PNS). © 2007 Wiley-Liss, Inc.
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axonal regulation of schwann cell integrin expression suggests a role for alpha 6 beta 4 in Myelination
Journal of Cell Biology, 1993Co-Authors: Steven Einheber, Teresa A Milner, Filippo G Giancotti, James L. SalzerAbstract:Ensheathment and Myelination of axons by Schwann cells in the peripheral nervous system requires contact with a basal lamina. The molecular mechanism(s) by which the basal lamina promotes Myelination is not known but is likely to reflect the activity of integrins expressed by Schwann cells. To initiate studies on the role of integrins during Myelination, we characterized the expression of two integrin subunits, beta 1 and beta 4, in an in vitro Myelination system and compared their expression to that of the glial adhesion molecule, the myelin-associated glycoprotein (MAG). In the absence of neurons, Schwann cells express significant levels of beta 1 but virtually no beta 4 or MAG. When Schwann cells are cocultured with dorsal root ganglia neurons under conditions promoting Myelination, expression of beta 4 and MAG increased dramatically in myelinating cells, whereas beta 1 levels remained essentially unchanged. (In general agreement with these findings, during peripheral nerve development in vivo, beta 4 levels also increase during the period of Myelination in sharp contrast to beta 1 levels which show a striking decrease.) In cocultures of neurons and Schwann cells, beta 4 and MAG appear to colocalize in nascent myelin sheaths but have distinct distributions in mature sheaths, with beta 4 concentrated in the outer plasma membrane of the Schwann cell and MAG localized to the inner (periaxonal) membrane. Surprisingly, beta 4 is also present at high levels with MAG in Schmidt-Lanterman incisures. Immunoprecipitation studies demonstrated that primary Schwann cells express beta 1 in association with the alpha 1 and alpha 6 subunits, while myelinating Schwann cells express alpha 6 beta 4 and possibly alpha 1 beta 1. beta 4 is also downregulated during Wallerian degeneration in vitro, indicating that its expression requires continuous Schwann cell contact with the axon. These results indicate that axonal contact induces the expression of beta 4 during Schwann cell Myelination and suggest that alpha 6 beta 4 is an important mediator of the interactions of myelinating Schwann cells with the basal lamina.
David A Lyons - One of the best experts on this subject based on the ideXlab platform.
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Myelination induces axonal hotspots of synaptic vesicle fusion that promote sheath growth
Current Biology, 2021Co-Authors: Rafael G Almeida, William S Talbot, Jill M Williamson, Megan E Madden, Jason J Early, Matthew G Voas, Isaac H. Bianco, David A LyonsAbstract:Summary Myelination of axons by oligodendrocytes enables fast saltatory conduction. Oligodendrocytes are responsive to neuronal activity, which has been shown to induce changes to myelin sheaths, potentially to optimize conduction and neural circuit function. However, the cellular bases of activity-regulated Myelination in vivo are unclear, partly due to the difficulty of analyzing individual myelinated axons over time. Activity-regulated Myelination occurs in specific neuronal subtypes and can be mediated by synaptic vesicle fusion, but several questions remain: it is unclear whether vesicular fusion occurs stochastically along axons or in discrete hotspots during Myelination and whether vesicular fusion regulates myelin targeting, formation, and/or growth. It is also unclear why some neurons, but not others, exhibit activity-regulated Myelination. Here, we imaged synaptic vesicle fusion in individual neurons in living zebrafish and documented robust vesicular fusion along axons during Myelination. Surprisingly, we found that axonal vesicular fusion increased upon and required Myelination. We found that axonal vesicular fusion was enriched in hotspots, namely the heminodal non-myelinated domains into which sheaths grew. Blocking vesicular fusion reduced the stable formation and growth of myelin sheaths, and chemogenetically stimulating neuronal activity promoted sheath growth. Finally, we observed high levels of axonal vesicular fusion only in neuronal subtypes that exhibit activity-regulated Myelination. Our results identify a novel “feedforward” mechanism whereby the process of Myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, consolidates sheath growth along specific axons selected for Myelination.
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individual neuronal subtypes exhibit diversity in cns Myelination mediated by synaptic vesicle release
Current Biology, 2016Co-Authors: Sigrid Koudelka, William S Talbot, Matthew G Voas, Marion Baraban, Rafael G Almeida, Jan Soetaert, Martin P Meyer, David A LyonsAbstract:Regulation of Myelination by oligodendrocytes in the CNS has important consequences for higher-order nervous system function (e.g., [1-4]), and there is growing consensus that neuronal activity regulates CNS Myelination (e.g., [5-9]) through local axon-oligodendrocyte synaptic-vesicle-release-mediated signaling [10-12]. Recent analyses have indicated that Myelination along axons of distinct neuronal subtypes can differ [13, 14], but it is not known whether regulation of Myelination by activity is common to all neuronal subtypes or only some. This limits insight into how specific neurons regulate their own conduction. Here, we use a novel fluorescent fusion protein reporter to study Myelination along the axons of distinct neuronal subtypes over time in zebrafish. We find that the axons of reticulospinal and commissural primary ascending (CoPA) neurons are among the first myelinated in the zebrafish CNS. To investigate how activity regulates Myelination by different neuronal subtypes, we express tetanus toxin (TeNT) in individual reticulospinal or CoPA neurons to prevent synaptic vesicle release. We find that the axons of individual tetanus toxin expressing reticulospinal neurons have fewer myelin sheaths than controls and that their myelin sheaths are 50% shorter than controls. In stark contrast, Myelination along tetanus-toxin-expressing CoPA neuron axons is entirely normal. These results indicate that while some neuronal subtypes modulate Myelination by synaptic vesicle release to a striking degree in vivo, others do not. These data have implications for our understanding of how different neurons regulate Myelination and thus their own function within specific neuronal circuits.
Lisbeth S Laursen - One of the best experts on this subject based on the ideXlab platform.
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ephrin a1 epha4 signaling negatively regulates Myelination in the central nervous system
Glia, 2018Co-Authors: Mette Harboe, Julie Torvundjensen, Kasper Kjaersorensen, Lisbeth S LaursenAbstract:During development of the central nervous system not all axons are myelinated, and axons may have distinct Myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits Myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases Myelination, whereas Myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced Myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of Myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.
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translation of myelin basic protein mrna in oligodendrocytes is regulated by integrin activation and hnrnp k
Journal of Cell Biology, 2011Co-Authors: Lisbeth S Laursen, Colin W Chan, Charles FfrenchconstantAbstract:Myelination in the central nervous system provides a unique example of how cells establish asymmetry. The myelinating cell, the oligodendrocyte, extends processes to and wraps multiple axons of different diameter, keeping the number of wraps proportional to the axon diameter. Local regulation of protein synthesis represents one mechanism used to control the different requirements for myelin sheath at each axo–glia interaction. Prior work has established that β1-integrins are involved in the axoglial interactions that initiate Myelination. Here, we show that integrin activation regulates translation of a key sheath protein, myelin basic protein (MBP), by reversing the inhibitory effect of the mRNA 3′UTR. During oligodendrocyte differentiation and Myelination α6β1-integrin interacts with hnRNP-K, an mRNA-binding protein, which binds to MBP mRNA and translocates from the nucleus to the myelin sheath. Furthermore, knockdown of hnRNP-K inhibits MBP protein synthesis during Myelination. Together, these results identify a novel pathway by which axoglial adhesion molecules coordinate MBP synthesis with myelin sheath formation.
