Understanding Of Myelination Research Articles

SOX10-regulated promoter use defines isoform-specific gene expression in Schwann cells

BackgroundMulticellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms. Schwann cells—the myelinating cells of the peripheral nervous system (PNS)—exhibit a specialized gene expression profile directed by the transcription factor SOX10, which is essential for PNS myelination. SOX10 regulates promoter elements associated with unique TSSs and gene isoforms at several target loci, implicating SOX10-mediated, isoform-specific gene expression in Schwann cell function. Here, we report on genome-wide efforts to identify SOX10-regulated promoters and TSSs in Schwann cells to prioritize genes and isoforms for further study.ResultsWe performed global TSS analyses and mined previously reported ChIP-seq datasets to assess the activity of SOX10-bound promoters in three models: (i) an adult mammalian nerve; (ii) differentiating primary Schwann cells, and (iii) cultured Schwann cells with ablated SOX10 function. We explored specific characteristics of SOX10-dependent TSSs, which provides confidence in defining them as SOX10 targets. Finally, we performed functional studies to validate our findings at four previously unreported SOX10 target loci: ARPC1A, CHN2, DDR1, and GAS7. These findings suggest roles for the associated SOX10-regulated gene products in PNS myelination.ConclusionsIn sum, we provide comprehensive computational and functional assessments of SOX10-regulated TSS use in Schwann cells. The data presented in this study will stimulate functional studies on the specific mRNA and protein isoforms that SOX10 regulates, which will improve our understanding of myelination in the peripheral nerve.

Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases.

The mechanisms regulating differentiation of multipotent oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs) are critical to our understanding of myelination and remyelination. Following acute demyelination in the central nervous system, adult OPCs migrate to the injury site, differentiate into OLs and generate new myelin sheaths. A common feature of regenerative processes is the fact that remyelination efficiency declines with aging and, accounts for the observation that chronic demyelinating diseases like multiple sclerosis (MS) are characterized by an ineffective remyelination. Without doubt, impairment of OPC differentiation is an essential determinant of the aging effects in remyelination. However, spontaneous remyelination is limited in demyelinating diseases such as MS, owing in part to the failure of adult OPCs to differentiate into myelinating OLs. The inability to restore myelin after injury compromises axon integrity and renders them vulnerable to degeneration. Although the genes that regulate the proliferation and differentiation of OPCs during development have been intensively studied, relatively little is known about the molecular signals that regulate the function of adult OPCs after demyelination. Elucidating the mechanisms regulating OPC differentiation are key to identifying pharmacological targets for remyelination-enhancing therapy. This review will discuss OPC biology, myelination, and possible pharmacological targets for promoting the differentiation of OPCs as a strategy to enhance remyelination, including the potential for nanoscale delivery.

Recent Advances in Live Imaging of Cells of the Oligodendrocyte Lineage.

Myelination is an important process that takes place also in the periphery during development and in theadulthood. Myelin serves as an electric isolator for axons, leading to a fast conduction of the action potential, and provides trophic support for the axon, both aspects highly important for the proper function of the nervous system. In the central nervous system, myelination starts shortly after birth and cells from the oligodendrocyte lineage tightly regulate this process during the whole life span. Initially, it was thought that under physiological conditions myelin generation only occurs in early postnatal development and that myelination stops at early adult ages. Historically, the process of myelination has mainly been studied in fixed tissue, and predominantly analyzed by electron microscopy, bringing valuable insights in the structure and distribution of myelin in the central nervous system. Nevertheless, the outdated notion of the static nature of myelin during adulthood was challenged in the past decades by the development of new techniques bringing in a new picture of a lively structure that is in constant remodeling under physiological and disease conditions. As fixed tissue can only provide information at a specific timepoint, the necessity of new techniques to study this process in vivo has become clear. In this chapter, we will review some of the latest techniques developed in order to study myelin and the oligodendrocyte lineage, as these cells are important for the formation and restructuration of the myelin. We will also introduce a protocol to prepare a cranial window to study NG2-glia (also known as oligodendrocyte progenitor cells) of the cerebral cortex in vivo, by 2-photon laser scanning microscopy. However, this technique can also be performed to study other cell populations or structures such as myelin, which will be discussed in this chapter as well. Despite being simple, this protocol has shown to be powerful to study the oligodendrocyte lineage and potentially is applicable to study myelin in vivo, which could turn into a key technique in the understanding of myelination and other functions that the oligodendrocyte lineage might have under physiological and disease conditions.

SNX27, a protein involved in down syndrome, regulates GPR17 trafficking and oligodendrocyte differentiation.

The G protein-coupled receptor 17 (GPR17) plays crucial roles in myelination. It is highly expressed during transition of oligodendrocyte progenitor cells to immature oligodendrocytes, but, after this stage, it must be down-regulated to allow generation of mature myelinating cells. After endocytosis, GPR17 is sorted into lysosomes for degradation or recycled to the plasma membrane. Balance between degradation and recycling is important for modulation of receptor levels at the cell surface and thus for the silencing/activation of GPR17-signaling pathways that, in turn, affect oligodendrocyte differentiation. The molecular mechanisms at the basis of these processes are still partially unknown and their characterization will allow a better understanding of myelination and provide cues to interpret the consequences of GPR17 dysfunction in diseases. Here, we demonstrate that the endocytic trafficking of GPR17 is mediated by the interaction of a type I PDZ-binding motif located at the C-terminus of the receptor and SNX27, a recently identified protein of the endosome-associated retromer complex and whose functions in oligodendrocytes have never been studied. SNX27 knock-down significantly reduces GPR17 plasma membrane recycling in differentiating oligodendrocytes while accelerating cells' terminal maturation. Interestingly, trisomy-linked down-regulation of SNX27 expression in the brain of Ts65Dn mice, a model of Down syndrome, correlates with a decrease in GPR17(+) cells and an increase in mature oligodendrocytes, which, however, fail in reaching full maturation, eventually leading to hypomyelination. Our data demonstrate that SNX27 modulates GPR17 plasma membrane recycling and stability, and that disruption of the SNX27/GPR17 interaction might contribute to pathological oligodendrocyte differentiation defects. GLIA 2016. GLIA 2016;64:1437-1460.

Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival.

During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS.

Outside-in & Inside-out Signaling in Integrins: The Key Players in Schwann Cell Biology

Event Abstract Back to Event Outside-in & Inside-out Signaling in Integrins: The Key Players in Schwann Cell Biology Lina Aires1*, Laura Montani1 and Joao B. Relvas1 1 Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Portugal Myelination is essential for the normal development of the nervous system and greatly increases the conduction velocity of the nervous impulse. Control of myelination derives, at least in part, from signals originated within the extracellular environment from which growth factors and proteins of the extracellular matrix (ECM) are essential components.There is a significant body of evidence showing that during peripheral nervous system (PNS) development Schwann cells (SCs) need to interpret different extracellular cues to regulate their migration, proliferation and the remarkable morphological changes associated with myelination of axons. Recruitment of cytoskeleton and signaling molecules to cell matrix contact sites, where they link the actin cytoskeleton to the ECM, mediates signal transduction between the extracellular and the intracellular compartments (outside-in signaling). Among the integrins, the β1-integrin subunit is part of many integrin heterodimers and in Schwann cells the genetic deletion of the β1-integrin subunit gene causes defects in SC- axon contact and impairs the capacity of SCs to extend cytoplasmic processes into embryonic axons bundles to establish one-to-one relationships with individual axons, a process referred to as radial sorting.Our work focus the role of β1-integrins together with its interacting partners of the IPP complex (integrin- linked-kinase, PINCH and Parvin) and different Rho GTPases in Schwann cells biology during the development of the peripheral nervous system.Insights into such mechanisms will hopefully help us to better understanding of myelination and may suggest therapeutic approaches to Peripheral Neuropathies. Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neuronal Communication Citation: Aires L, Montani L and Relvas JB (2009). Outside-in & Inside-out Signaling in Integrins: The Key Players in Schwann Cell Biology. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.140 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Aug 2009; Published Online: 11 Aug 2009. * Correspondence: Lina Aires, Universidade do Porto, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal, lina.adriana@ibmc.up.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Lina Aires Laura Montani Joao B Relvas Google Lina Aires Laura Montani Joao B Relvas Google Scholar Lina Aires Laura Montani Joao B Relvas PubMed Lina Aires Laura Montani Joao B Relvas Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A genetic screen identifies genes essential for development of myelinated axons in zebrafish

The myelin sheath insulates axons in the vertebrate nervous system, allowing rapid propagation of action potentials via saltatory conduction. Specialized glial cells, termed Schwann cells in the PNS and oligodendrocytes in the CNS, wrap axons to form myelin, a compacted, multilayered sheath comprising specific proteins and lipids. Disruption of myelinated axons causes human diseases, including multiple sclerosis and Charcot–Marie–Tooth peripheral neuropathies. Despite the progress in identifying human disease genes and other mutations disrupting glial development and myelination, many important unanswered questions remain about the mechanisms that coordinate the development of myelinated axons. To address these questions, we began a genetic dissection of myelination in zebrafish. Here we report a genetic screen that identified 13 mutations, which define 10 genes, disrupting the development of myelinated axons. We present the initial characterization of seven of these mutations, defining six different genes, along with additional characterization of mutations that we have described previously. The different mutations affect the PNS, the CNS, or both, and phenotypic analyses indicate that the genes affect a wide range of steps in glial development, from fate specification through terminal differentiation. The analysis of these mutations will advance our understanding of myelination, and the mutants will serve as models of human diseases of myelin.

Insertion of a Retrotransposon inMbpDisrupts mRNA Splicing and Myelination in a New Mutant Rat

Our understanding of myelination has been greatly enhanced via the study of spontaneous mutants that harbor a defect in a gene encoding one of the major myelin proteins (myelin mutants). In this study, we describe a unique genetic defect in a new myelin mutant called the Long Evans shaker (les) rat that causes severe dysmyelination of the CNS. Myelin deficits result from disruption of the myelin basic protein (Mbp) gene caused by the insertion of an endogenous retrotransposon [early transposons (ETn) element] into a noncoding region (intron 3) of the gene. The ETn element alters the normal splicing dynamics of MBP mRNA, leading to a dramatic reduction in the levels of full-length isoforms (<5% of normal) and the appearance of improperly spliced, chimeric transcripts. Although these aberrant transcripts contain proximal coding regions of the MBP gene (exons 1-3), they are unable to encode functional proteins required to maintain the structural integrity of the myelin sheath. These chimeric transcripts seem capable, however, of producing the necessary signal to initiate and coordinate myelin gene expression because normal numbers of mature oligodendrocytes synthesizing abundant levels of other myelin proteins are present in the mutant CNS. The les rat is thus an excellent model to study alternative functions of MBP beyond its well characterized role in myelin compaction.