The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Kristjan R. Jessen - One of the best experts on this subject based on the ideXlab platform.
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repair Schwann Cell update adaptive reprogramming emt and stemness in regenerating nerves
Glia, 2019Co-Authors: Kristjan R. Jessen, Peter ArthurfarrajAbstract:Schwann Cells respond to nerve injury by Cellular reprogramming that generates Cells specialized for promoting regeneration and repair. These repair Cells clear redundant myelin, attract macrophages, support survival of damaged neurons, encourage axonal growth, and guide axons back to their targets. There are interesting parallels between this response and that found in other tissues. At the Cellular level, many other tissues also react to injury by Cellular reprogramming, generating Cells specialized to promote tissue homeostasis and repair. And at the molecular level, a common feature possessed by Schwann Cells and many other Cells is the injury-induced activation of genes associated with epithelial-mesenchymal transitions and stemness, differentiation states that are linked to Cellular plasticity and that help injury-induced tissue remodeling. The number of signaling systems regulating Schwann Cell plasticity is rapidly increasing. Importantly, this includes mechanisms that are crucial for the generation of functional repair Schwann Cells and nerve regeneration, although they have no or a minor role elsewhere in the Schwann Cell lineage. This encourages the view that selective tools can be developed to control these particular Cells, amplify their repair supportive functions and prevent their deterioration. In this review, we discuss the emerging similarities between the injury response seen in nerves and in other tissues and survey the transcription factors, epigenetic mechanisms, and signaling cascades that control repair Schwann Cells, with emphasis on systems that selectively regulate the Schwann Cell injury response.
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Isolation of Schwann Cell Precursors from Rodents.
Methods of Molecular Biology, 2018Co-Authors: Rhona Mirsky, Kristjan R. JessenAbstract:Schwann Cell precursors are the first defined stage in the generation of Schwann Cells from the neural crest and represent the glial Cell of embryonic nerves. Highly pure cultures of these Cells can be obtained by enzymatic dissociation of nerves dissected from the limbs of 14- or 12-day-old rat and mouse embryos, respectively. Since Schwann Cell precursors, unlike Schwann Cells, are acutely dependent on axonal signals for survival, they require addition of trophic factors, typically β-neuregulin-1, for maintenance in Cell culture. Under these conditions they convert to Schwann Cells on schedule, within about 4 days.
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the repair Schwann Cell and its function in regenerating nerves
The Journal of Physiology, 2016Co-Authors: Kristjan R. Jessen, Rhona MirskyAbstract:Nerve injury triggers the conversion of myelin and non-myelin (Remak) Schwann Cells to a Cell phenotype specialized to promote repair. Distal to damage, these repair Schwann Cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann Cells involves de-differentiation together with alternative differentiation, or activation, a combination that is typical of Cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury-induced Schwann Cell reprogramming involves down-regulation of myelin genes combined with activation of a set of repair-supportive features, including up-regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann Cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c-Jun, which is rapidly up-regulated in Schwann Cells after injury. In the absence of c-Jun, damage results in the formation of a dysfunctional repair Cell, neuronal death and failure of functional recovery. c-Jun, although not required for Schwann Cell development, is therefore central to the reprogramming of myelin and non-myelin (Remak) Schwann Cells to repair Cells after injury. In future, the signalling that specifies this Cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann Cell phenotype can be developed.
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p38 MAPK Activation Promotes Denervated Schwann Cell Phenotype and Functions as a Negative Regulator of Schwann Cell Differentiation and Myelination
The Journal of Neuroscience, 2012Co-Authors: David P. Yang, Kristjan R. Jessen, Rhona Mirsky, Jihyun Kim, Neeraja Syed, Young-john Tung, A Bhaskaran, Thomas Mindos, Patrice Maurel, David B. ParkinsonAbstract:Physical damage to the peripheral nerves triggers Schwann Cell injury response in the distal nerves in an event termed Wallerian degeneration: the Schwann Cells degrade their myelin sheaths and dedifferentiate, reverting to a phenotype that supports axon regeneration and nerve repair. The molecular mechanisms regulating Schwann Cell plasticity in the PNS remain to be elucidated. Using both in vivo and in vitro models for peripheral nerve injury, here we show that inhibition of p38 mitogen-activated protein kinase (MAPK) activity in mice blocks Schwann Cell demyelination and dedifferentiation following nerve injury, suggesting that the kinase mediates the injury signal that triggers distal Schwann Cell injury response. In myelinating cocultures, p38 MAPK also mediates myelin breakdown induced by Schwann Cell growth factors, such as neuregulin and FGF-2. Furthermore, ectopic activation of p38 MAPK is sufficient to induce myelin breakdown and drives differentiated Schwann Cells to acquire phenotypic features of immature Schwann Cells. We also show that p38 MAPK concomitantly functions as a negative regulator of Schwann Cell differentiation: enforced p38 MAPK activation blocks cAMP-induced expression of Krox 20 and myelin proteins, but induces expression of c-Jun. As expected of its role as a negative signal for myelination, inhibition of p38 MAPK in cocultures promotes myelin formation by increasing the number as well as the length of individual myelin segments. Altogether, our data identify p38 MAPK as an important regulator of Schwann Cell plasticity and differentiation.
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novel signals controlling embryonic Schwann Cell development myelination and dedifferentiation
Journal of The Peripheral Nervous System, 2008Co-Authors: Rhona Mirsky, Ashwin Woodhoo, A Bhaskaran, David B. Parkinson, Peter Arthurfarraj, Kristjan R. JessenAbstract:Immature Schwann Cells found in perinatal rodent nerves are generated from Schwann Cell precursors (SCPs) that originate from the neural crest. Immature Schwann Cells generate the myelinating and non-myelinating Schwann Cells of adult nerves. When axons degenerate following injury, Schwann Cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature Cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann Cell dedifferentiation involves activation of specific receptors, intraCellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann Cell, times Schwann Cell generation, controls Schwann Cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann Cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann Cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann Cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.
Rhona Mirsky - One of the best experts on this subject based on the ideXlab platform.
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Isolation of Schwann Cell Precursors from Rodents.
Methods of Molecular Biology, 2018Co-Authors: Rhona Mirsky, Kristjan R. JessenAbstract:Schwann Cell precursors are the first defined stage in the generation of Schwann Cells from the neural crest and represent the glial Cell of embryonic nerves. Highly pure cultures of these Cells can be obtained by enzymatic dissociation of nerves dissected from the limbs of 14- or 12-day-old rat and mouse embryos, respectively. Since Schwann Cell precursors, unlike Schwann Cells, are acutely dependent on axonal signals for survival, they require addition of trophic factors, typically β-neuregulin-1, for maintenance in Cell culture. Under these conditions they convert to Schwann Cells on schedule, within about 4 days.
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the repair Schwann Cell and its function in regenerating nerves
The Journal of Physiology, 2016Co-Authors: Kristjan R. Jessen, Rhona MirskyAbstract:Nerve injury triggers the conversion of myelin and non-myelin (Remak) Schwann Cells to a Cell phenotype specialized to promote repair. Distal to damage, these repair Schwann Cells provide the necessary signals and spatial cues for the survival of injured neurons, axonal regeneration and target reinnervation. The conversion to repair Schwann Cells involves de-differentiation together with alternative differentiation, or activation, a combination that is typical of Cell type conversions often referred to as (direct or lineage) reprogramming. Thus, injury-induced Schwann Cell reprogramming involves down-regulation of myelin genes combined with activation of a set of repair-supportive features, including up-regulation of trophic factors, elevation of cytokines as part of the innate immune response, myelin clearance by activation of myelin autophagy in Schwann Cells and macrophage recruitment, and the formation of regeneration tracks, Bungner's bands, for directing axons to their targets. This repair programme is controlled transcriptionally by mechanisms involving the transcription factor c-Jun, which is rapidly up-regulated in Schwann Cells after injury. In the absence of c-Jun, damage results in the formation of a dysfunctional repair Cell, neuronal death and failure of functional recovery. c-Jun, although not required for Schwann Cell development, is therefore central to the reprogramming of myelin and non-myelin (Remak) Schwann Cells to repair Cells after injury. In future, the signalling that specifies this Cell requires further analysis so that pharmacological tools that boost and maintain the repair Schwann Cell phenotype can be developed.
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p38 MAPK Activation Promotes Denervated Schwann Cell Phenotype and Functions as a Negative Regulator of Schwann Cell Differentiation and Myelination
The Journal of Neuroscience, 2012Co-Authors: David P. Yang, Kristjan R. Jessen, Rhona Mirsky, Jihyun Kim, Neeraja Syed, Young-john Tung, A Bhaskaran, Thomas Mindos, Patrice Maurel, David B. ParkinsonAbstract:Physical damage to the peripheral nerves triggers Schwann Cell injury response in the distal nerves in an event termed Wallerian degeneration: the Schwann Cells degrade their myelin sheaths and dedifferentiate, reverting to a phenotype that supports axon regeneration and nerve repair. The molecular mechanisms regulating Schwann Cell plasticity in the PNS remain to be elucidated. Using both in vivo and in vitro models for peripheral nerve injury, here we show that inhibition of p38 mitogen-activated protein kinase (MAPK) activity in mice blocks Schwann Cell demyelination and dedifferentiation following nerve injury, suggesting that the kinase mediates the injury signal that triggers distal Schwann Cell injury response. In myelinating cocultures, p38 MAPK also mediates myelin breakdown induced by Schwann Cell growth factors, such as neuregulin and FGF-2. Furthermore, ectopic activation of p38 MAPK is sufficient to induce myelin breakdown and drives differentiated Schwann Cells to acquire phenotypic features of immature Schwann Cells. We also show that p38 MAPK concomitantly functions as a negative regulator of Schwann Cell differentiation: enforced p38 MAPK activation blocks cAMP-induced expression of Krox 20 and myelin proteins, but induces expression of c-Jun. As expected of its role as a negative signal for myelination, inhibition of p38 MAPK in cocultures promotes myelin formation by increasing the number as well as the length of individual myelin segments. Altogether, our data identify p38 MAPK as an important regulator of Schwann Cell plasticity and differentiation.
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novel signals controlling embryonic Schwann Cell development myelination and dedifferentiation
Journal of The Peripheral Nervous System, 2008Co-Authors: Rhona Mirsky, Ashwin Woodhoo, A Bhaskaran, David B. Parkinson, Peter Arthurfarraj, Kristjan R. JessenAbstract:Immature Schwann Cells found in perinatal rodent nerves are generated from Schwann Cell precursors (SCPs) that originate from the neural crest. Immature Schwann Cells generate the myelinating and non-myelinating Schwann Cells of adult nerves. When axons degenerate following injury, Schwann Cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature Cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann Cell dedifferentiation involves activation of specific receptors, intraCellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann Cell, times Schwann Cell generation, controls Schwann Cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann Cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann Cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann Cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.
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Schwann Cell Development
Myelin Biology and Disorders, 2007Co-Authors: Kristjan R. Jessen, Rhona MirskyAbstract:Publisher Summary This chapter describes the development of glial Cells in embryonic and early neonatal nerve trunks of rodents. It examines the origin of the Schwann Cell lineage and the Cellular transformations that lead to the appearance of immature Schwann Cells, the predominant glial Cell in rodent nerves at birth. There are three main transitions in the Schwann Cell lineage. First is the formation of Schwann Cell precursors from undifferentiated migrating neural crest Cells. This is characterized by the appearance of several differentiation markers and by the assumption of an intimate relationship with axons. Second is precursor-Schwann Cell transition. This is characterized by the appearance of a number of differentiation markers and the establishment of autocrine survival circuits. Finally, the formation of mature myelinating and nonmyelinating Schwann Cells. This involves radical morphological and molecular changes, particularly in myelinating Cells. Furthermore, this chapter also discusses the extraCellular signaling molecules and matrix receptors that control this system and the transcription factors that are known, or suspected, to be important in regulating embryonic Schwann Cell development and the onset of myelination.
Carmen Birchmeier - One of the best experts on this subject based on the ideXlab platform.
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wnt rspondin β catenin signals control axonal sorting and lineage progression in Schwann Cell development
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Tamara Grigoryan, Carmen Birchmeier, Alistair N Garratt, Klausarmin Nave, Simone Stein, Jingjing Qi, Hagen Wende, Walter BirchmeierAbstract:During late Schwann Cell development, immature Schwann Cells segregate large axons from bundles, a process called “axonal radial sorting.” Here we demonstrate that canonical Wnt signals play a critical role in radial sorting and assign a role to Wnt and Rspondin ligands in this process. Mice carrying β-catenin loss-of-function mutations show a delay in axonal sorting; conversely, gain-of-function mutations result in accelerated sorting. Sorting deficits are accompanied by abnormal process extension, differentiation, and aberrant Cell cycle exit of the Schwann Cells. Using primary cultured Schwann Cells, we analyze the upstream effectors, Wnt and Rspondin ligands that initiate signaling, and downstream genetic programs that mediate the Wnt response. Our analysis contributes to a better understanding of the mechanisms of Schwann Cell development and fate decisions.
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nrg1 erbb signaling networks in Schwann Cell development and myelination
Seminars in Cell & Developmental Biology, 2010Co-Authors: Jason M Newbern, Carmen BirchmeierAbstract:Neuregulin-1 (Nrg1) provides a key axonal signal that regulates Schwann Cell proliferation, migration and myelination through binding to ErbB2/3 receptors. The analysis of a number of genetic models has unmasked fundamental mechanisms underlying the specificity of the Nrg1/ErbB signaling axis. Differential expression of Nrg1 isoforms, Nrg1 processing, and ErbB receptor localization and trafficking represent important regulatory themes in the control of Nrg1/ErbB function. Nrg1 binding to ErbB2/3 receptors results in the activation of intraCellular signal transduction pathways that initiate changes in Schwann Cell behavior. Here, we review data that has defined the role of key Nrg1/ErbB signaling components like Shp2, ERK1/2, FAK, Rac1/Cdc42 and calcineurin in development of the Schwann Cell lineage in vivo. Many of these regulators receive converging signals from other cues that are provided by Notch, integrin or G-protein coupled receptors. Signaling by multiple extraCellular factors may act as key modifiers and allow Schwann Cells at different developmental stages to respond in distinct manners to the Nrg1/ErbB signal.
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neuregulin 1 a key axonal signal that drives Schwann Cell growth and differentiation
Glia, 2008Co-Authors: Carmen Birchmeier, Klausarmin NaveAbstract:Interactions between neuronal and glial Cells are crucial for establishing a functional nervous system. Many aspects of Schwann Cell development and physiology are regulated by neuronal signals; possibly the most spectacular is the elaboration of the myelin sheath. An extensive line of research has revealed that one neuronal factor, termed "neuregulin", promotes Schwann Cell growth and survival, migration along the extending axon, and myelination. The versatility of glial responses elicited by this factor is thus clearly astounding.
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neuregulin 1 a key axonal signal that drives Schwann Cell growth and differentiation
Glia, 2008Co-Authors: Carmen Birchmeier, Klausarmin NaveAbstract:Interactions between neuronal and glial Cells are crucial for establishing a functional nervous system. Many aspects of Schwann Cell development and physiology are regulated by neuronal signals; possibly the most spectacular is the elaboration of the myelin sheath. An extensive line of research has revealed that one neuronal factor, termed “neuregulin”, promotes Schwann Cell growth and survival, migration along the extending axon, and myelination. The versatility of glial responses elicited by this factor is thus clearly astounding. © 2008 Wiley-Liss, Inc.
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a dual role of erbb2 in myelination and in expansion of the Schwann Cell precursor pool
Journal of Cell Biology, 2000Co-Authors: Alistair N Garratt, Patrick Charnay, Octavian Voiculescu, Piotr Topilko, Carmen BirchmeierAbstract:Neuregulin-1 provides an important axonally derived signal for the survival and growth of developing Schwann Cells, which is transmitted by the ErbB2/ErbB3 receptor tyrosine kinases. Null mutations of the neuregulin-1, erbB2, or erbB3 mouse genes cause severe deficits in early Schwann Cell development. Here, we employ Cre-loxP technology to introduce erbB2 mutations late in Schwann Cell development, using a Krox20-cre allele. Cre-mediated erbB2 ablation occurs perinatally in peripheral nerves, but already at E11 within spinal roots. The mutant mice exhibit a widespread peripheral neuropathy characterized by abnormally thin myelin sheaths, containing fewer myelin wraps. In addition, in spinal roots the Schwann Cell precursor pool is not correctly established. Thus, the Neuregulin signaling system functions during multiple stages of Schwann Cell development and is essential for correct myelination. The thickness of the myelin sheath is determined by the axon diameter, and we suggest that trophic signals provided by the nerve determine the number of times a Schwann Cell wraps an axon.
James L. Salzer - One of the best experts on this subject based on the ideXlab platform.
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necl 4 cadm4 recruits par 3 to the Schwann Cell adaxonal membrane
Glia, 2019Co-Authors: Xiaosong Meng, Patrice Maurel, Isabel Lam, Corey Heffernan, Michael A Stiffler, Gavin Mcbeath, James L. SalzerAbstract:Interactions between axons and Schwann Cells are essential for the acquisition of Schwann Cell radial and longitudinal polarity and myelin sheath assembly. In the internode, the largest of these longitudinal domains, axon-Schwann Cell interactions are mediated by the Nectin-like (Necl) Cell adhesion proteins, also known as SynCAMs or Cadms. In particular, Necl-1/Cadm3 expressed on the axon surface binds to Necl-4/Cadm4 expressed along the adaxonal membrane of myelinating Schwann Cells. Necl-4 promotes myelination in vitro and is required for the timely onset of myelination and the fidelity of the organization of the myelin sheath and the internode in vivo. A key question is the identity of the downstream effectors of Necl-4 that mediate its effects. The cytoplasmic terminal region (CTR) of Necl-4 contains a PDZ-domain binding motif. Accordingly, we used the CTR of Necl-4 in an unbiased proteomic screen of PDZ-domain proteins. We identify Par-3, a multi-PDZ domain containing protein of the Par-aPKC polarity complex previously implicated in myelination, as an interacting protein. Necl-4 and Par-3 are colocalized along the inner Schwann Cell membrane and coprecipitate from Schwann Cell lysates. The CTR of Necl-4 binds to the first PDZ domain of Par-3 thereby recruiting Par-3 to sites of Necl-4/Necl-1 interaction. Knockdown of Necl-4 perturbs Par-3 localization to the inner membrane of Schwann Cells in myelinating co-cultures. These findings implicate interactions of Necl-1/Necl-4 in the recruitment of Par-3 to the Schwann Cell adaxonal membrane and the establishment of Schwann Cell radial polarity.
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Schwann Cell Myelination
Cold Spring Harbor Perspectives in Biology, 2015Co-Authors: James L. SalzerAbstract:Abstract Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann Cells. Extrinsic signals from the axon, and the extraCellular matrix, drive Schwann Cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann Cells. Recent findings into the extrinsic signals that drive Schwann Cell myelination, their cognate receptors, and the downstream intraCellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath.
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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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rho kinase regulates Schwann Cell myelination and formation of associated axonal domains
The Journal of Neuroscience, 2004Co-Authors: Carmen V Melendezvasquez, Steven Einheber, James L. SalzerAbstract:The myelin sheath forms by the spiral wrapping of a glial membrane around an axon. The mechanisms involved are poorly understood but are likely to involve coordinated changes in the glial Cell cytoskeleton. Because of its key role as a regulator of the cytoskeleton, we investigated the role of Rho kinase (ROCK), a major downstream effector of Rho, in Schwann Cell morphology, differentiation, and myelination. Pharmacologic inhibition of ROCK activity results in loss of microvilli and stress fibers in Schwann Cell cultures and strikingly aberrant myelination in Schwann Cell-neuron cocultures; there was no effect on Schwann Cell proliferation or differentiation. Treated Schwann Cells branch aberrantly and form multiple, small, independent myelin segments along the length of axons, each with associated nodes and paranodes. This organization partially resembles myelin formed by oligodendrocytes rather than the single long myelin sheath characteristic of Schwann Cells. ROCK regulates myosin light chain phosphorylation, which is robustly, but transiently, activated at the onset of myelination. These results support a key role of Rho through its effector ROCK in coordinating the movement of the glial membrane around the axon at the onset of myelination via regulation of myosin phosphorylation and actomyosin assembly. They also indicate that the molecular machinery that promotes the wrapping of the glial membrane sheath around the axon is distributed along the entire length of the internode.
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axonal regulation of Schwann Cell proliferation and survival and the initial events of myelination requires pi 3 kinase activity
The Journal of Neuroscience, 2000Co-Authors: Patrice Maurel, James L. SalzerAbstract:In this report, we have investigated the signaling pathways that are activated by, and mediate the effects of, the neuregulins and axonal contact in Schwann Cells. Phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase kinase (MAPK kinase) are strongly activated in Schwann Cells by glial growth factor (GGF), a soluble neuregulin, and by contact with neurite membranes; both kinase activities are also detected in Schwann Cell-DRG neuron cocultures. Inhibition of the PI 3-kinase, but not the MAP kinase, pathway reversibly inhibited Schwann Cell proliferation induced by GGF and neurites. Cultured Schwann Cells undergo apoptosis after serum deprivation and can be rescued by GGF or contact with neurites; these survival effects were also blocked by inhibition of PI 3-kinase. Finally, we have examined the role of these signaling pathways in Schwann Cell differentiation in cocultures. At early stages of coculture, inhibition of PI 3-kinase, but not MAPK kinase, blocked Schwann Cell elongation and subsequent myelination but did not affect laminin deposition. Later, after Schwann Cells established a one-to-one relationship with axons, inhibition of PI 3-kinase did not block myelin formation, but the myelin sheaths that formed were shorter, and the rate of myelin protein accumulation was markedly decreased. PI 3-kinase inhibition had no observable effect on the maintenance of myelin sheaths in mature myelinated cocultures. These results indicate that activation of PI 3-kinase by axonal factors, including the neuregulins, promotes Schwann Cell proliferation and survival and implicate PI 3-kinase in the early events of myelination.
Klausarmin Nave - One of the best experts on this subject based on the ideXlab platform.
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wnt rspondin β catenin signals control axonal sorting and lineage progression in Schwann Cell development
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Tamara Grigoryan, Carmen Birchmeier, Alistair N Garratt, Klausarmin Nave, Simone Stein, Jingjing Qi, Hagen Wende, Walter BirchmeierAbstract:During late Schwann Cell development, immature Schwann Cells segregate large axons from bundles, a process called “axonal radial sorting.” Here we demonstrate that canonical Wnt signals play a critical role in radial sorting and assign a role to Wnt and Rspondin ligands in this process. Mice carrying β-catenin loss-of-function mutations show a delay in axonal sorting; conversely, gain-of-function mutations result in accelerated sorting. Sorting deficits are accompanied by abnormal process extension, differentiation, and aberrant Cell cycle exit of the Schwann Cells. Using primary cultured Schwann Cells, we analyze the upstream effectors, Wnt and Rspondin ligands that initiate signaling, and downstream genetic programs that mediate the Wnt response. Our analysis contributes to a better understanding of the mechanisms of Schwann Cell development and fate decisions.
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hdac mediated deacetylation of nf κb is critical for Schwann Cell myelination
Nature Neuroscience, 2011Co-Authors: Ying Chen, Haesun A Kim, Haibo Wang, Sung Ok Yoon, Michael O Hottiger, John Svaren, Klausarmin Nave, Eric N OlsonAbstract:Schwann Cell myelination is tightly regulated by timely expression of key transcriptional regulators that respond to specific environmental cues, but the molecular mechanisms underlying such a process are poorly understood. We found that the acetylation state of NF-κB, which is regulated by histone deacetylases (HDACs) 1 and 2, is critical for orchestrating the myelination program. Mice lacking both HDACs 1 and 2 (HDAC1/2) exhibited severe myelin deficiency with Schwann Cell development arrested at the immature stage. NF-κB p65 became heavily acetylated in HDAC1/2 mutants, inhibiting the expression of positive regulators of myelination and inducing the expression of differentiation inhibitors. We observed that the NF-κB protein complex switched from associating with p300 to associating with HDAC1/2 as Schwann Cells differentiated. NF-κB and HDAC1/2 acted in a coordinated fashion to regulate the transcriptionally linked chromatin state for Schwann Cell myelination. Thus, our results reveal an HDAC-mediated developmental switch for controlling myelination in the peripheral nervous system.
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neuregulin 1 a key axonal signal that drives Schwann Cell growth and differentiation
Glia, 2008Co-Authors: Carmen Birchmeier, Klausarmin NaveAbstract:Interactions between neuronal and glial Cells are crucial for establishing a functional nervous system. Many aspects of Schwann Cell development and physiology are regulated by neuronal signals; possibly the most spectacular is the elaboration of the myelin sheath. An extensive line of research has revealed that one neuronal factor, termed "neuregulin", promotes Schwann Cell growth and survival, migration along the extending axon, and myelination. The versatility of glial responses elicited by this factor is thus clearly astounding.
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neuregulin 1 a key axonal signal that drives Schwann Cell growth and differentiation
Glia, 2008Co-Authors: Carmen Birchmeier, Klausarmin NaveAbstract:Interactions between neuronal and glial Cells are crucial for establishing a functional nervous system. Many aspects of Schwann Cell development and physiology are regulated by neuronal signals; possibly the most spectacular is the elaboration of the myelin sheath. An extensive line of research has revealed that one neuronal factor, termed “neuregulin”, promotes Schwann Cell growth and survival, migration along the extending axon, and myelination. The versatility of glial responses elicited by this factor is thus clearly astounding. © 2008 Wiley-Liss, Inc.
