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      Contact-Mediated Inhibition Between Oligodendrocyte Progenitor Cells and Motor Exit Point Glia Establishes the Spinal Cord Transition Zone

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      PLoS Biology

      Public Library of Science

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In vivo experiments in zebrafish determine that CNS-derived glial cells contribute to the myelinating population of cells in the PNS and ensure that CNS and PNS glia remain segregated.

          Abstract

          Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition.

          Author Summary

          The nervous system is often thought as two distinct halves: the central nervous system (CNS), which consists of the brain and spinal cord, and the peripheral nervous system (PNS), which includes the nerves that control movement and sense the environment. The cells within these two halves, however, do not commonly mix. To address how cells are segregated within these two compartments of the nervous system, we used live, transgenic zebrafish embryos to watch nerve development. Our study shows that CNS-residing myelinating glia (nonneuronal cells that wrap around nerves to ensure nerve impulse conduction) are restricted from entering the PNS by a cell we call motor exit point (MEP) glia. MEP glia originate from within the CNS, and then migrate into the PNS, divide, and produce cells that ensheath and myelinate spinal motor root axons. Ablation of MEP glia causes CNS glia to migrate inappropriately into the PNS, disrupting the normal boundary that is present between the CNS and PNS. Overall, the identification and characterization of MEP glia identifies an aspect of peripheral nerve composition that may be pertinent in human health and disease.

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          Most cited references 35

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          The origin and development of glial cells in peripheral nerves.

          During the development of peripheral nerves, neural crest cells generate myelinating and non-myelinating glial cells in a process that parallels gliogenesis from the germinal layers of the CNS. Unlike central gliogenesis, neural crest development involves a protracted embryonic phase devoted to the generation of, first, the Schwann cell precursor and then the immature Schwann cell, a cell whose fate as a myelinating or non-myelinating cell has yet to be determined. Embryonic nerves therefore offer a particular opportunity to analyse the early steps of gliogenesis from transient multipotent stem cells, and to understand how this process is integrated with organogenesis of peripheral nerves.
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            Regulation of oligodendrocyte differentiation and myelination.

            Despite the importance of myelin for the rapid conduction of action potentials, the molecular bases of oligodendrocyte differentiation and central nervous system (CNS) myelination are still incompletely understood. Recent results have greatly advanced this understanding, identifying new transcriptional regulators of myelin gene expression, elucidating vital roles for microRNAs in controlling myelination, and clarifying the extracellular signaling mechanisms that orchestrate the development of myelin. Studies have also demonstrated an unexpected level of plasticity of myelin in the adult CNS. These recent advances provide new insight into how remyelination may be stimulated in demyelinating disorders such as multiple sclerosis.
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              GFAP transgenic zebrafish.

              We have generated transgenic zebrafish that express green fluorescent protein (GFP) in glial cells driven by the zebrafish glial fibrillary acidic protein (GFAP) regulatory elements. Transgenic lines Tg(gfap:GFP) were generated from three founders; the results presented here are from the mi2001 line. GFP expression was first visible in the living embryo at the tail bud-stage, then in the developing brain by the 5-somite-stage ( approximately 12 h post-fertilization, hpf) and then spreading posteriorly along the developing spinal cord by the 12-somite stage (approximately 15 hpf). At 24 hpf GFP-expressing cells were in the retina and lens. By 72 hpf GFP expression levels were strong and localized to the glia of the brain, neural retina, spinal cord, and ventral spinal nerves, with moderate expression in the enteric nervous system and weaker levels in the olfactory sensory placode and otic capsule. GFP expression in glia co-localized with anti-GFAP antibodies, but did not co-localize with the neuronal antibodies HuC/D or calretinin in mature neurons.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                September 2014
                30 September 2014
                : 12
                : 9
                Affiliations
                Department of Biology, University of Virginia, Charlottesville, Virginia, United States of America
                Stanford University School of Medicine, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                The author(s) have made the following declarations about their contributions: Conceived and designed the experiments: CJS SK. Performed the experiments: CJS ADM TGW. Analyzed the data: CJS ADM TGW. Contributed reagents/materials/analysis tools: CJS ADM TGW. Contributed to the writing of the manuscript: CJS ADM TGW SK.

                Article
                PBIOLOGY-D-14-01371
                10.1371/journal.pbio.1001961
                4181976
                25268888

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 15
                Funding
                This work was supported by the National Institutes of Health ( http://www.ninds.nih.gov/) - NS072212 (S.K.), F32NS087791 (C.J.S.), and the March of Dimes ( http://www.marchofdimes.com/) - 5-FY11-90 (S.K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Nervous System
                Motor System
                Cell Biology
                Cell Motility
                Cell Migration
                Cellular Types
                Animal Cells
                Glial Cells
                Macroglial Cells
                Oligodendroglia
                Developmental Biology
                Neuroscience
                Cellular Neuroscience
                Neuroglial Development
                Developmental Neuroscience
                Organisms
                Animals
                Vertebrates
                Fishes
                Osteichthyes
                Zebrafish
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Life sciences

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