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      Sox10 is required for Schwann cell identity and progression beyond the immature Schwann cell stage

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          The Sox10 transcription factor is required to maintain as well as specify glial identity, adding new causes for the neuropathies associated with SOX10 mutations.


          Mutations in the transcription factor SOX10 cause neurocristopathies, including Waardenburg-Hirschsprung syndrome and peripheral neuropathies in humans. This is partly attributed to a requirement for Sox10 in early neural crest for survival, maintenance of pluripotency, and specification to several cell lineages, including peripheral glia. As a consequence, peripheral glia are absent in Sox10-deficient mice. Intriguingly, Sox10 continues to be expressed in these cells after specification. To analyze glial functions after specification, we specifically deleted Sox10 in immature Schwann cells by conditional mutagenesis. Mutant mice died from peripheral neuropathy before the seventh postnatal week. Nerve alterations included a thinned perineurial sheath, increased lipid and collagen deposition, and a dramatically altered cellular composition. Nerve conduction was also grossly aberrant, and neither myelinating nor nonmyelinating Schwann cells formed. Instead, axons of different sizes remained unsorted in large bundles. Schwann cells failed to develop beyond the immature stage and were unable to maintain identity. Thus, our study identifies a novel cause for peripheral neuropathies in patients with SOX10 mutations.

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          Most cited references 33

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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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            Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators.

            Members of the SOX family of transcription factors are found throughout the animal kingdom, are characterized by the presence of a DNA-binding HMG domain, and are involved in a diverse range of developmental processes. Previous attempts to group SOX genes and deduce their structural, functional, and evolutionary relationships have relied largely on complete or partial HMG box sequence of a limited number of genes. In this study, we have used complete HMG domain sequence, full-length protein structure, and gene organization data to study the pattern of evolution within the family. For the first time, a substantial number of invertebrate SOX sequences have been included in the analysis. We find support for subdivision of the family into groups A-H, as has been suggested in some previous studies, and for the assignment of two new groups, I and J. For vertebrate genes, it appears that relatedness as suggested by HMG domain sequence is congruent with relatedness as indicated by overall structure of the full-length protein and intron-exon structure of the genes. Most of the SOX groups identified in vertebrates were represented by a single SOX sequence in each invertebrate species studied. We have named anonymous sequences and, where appropriate, have suggested systematic names for some previously identified sequences. In addition, we identify an HMG domain signature motif which may be considered representative of the SOX family. Based on our data, we propose a robust phylogeny of SOX genes that reflects their evolutionary history in metazoans. Copyright 2000 Academic Press.
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              Krox-20 controls myelination in the peripheral nervous system.

              The molecular mechanisms controlling the process of myelination by Schwann cells remain elusive, despite recent progress in the identification and characterization of genes encoding myelin components (reviewed in ref. 1). We have created a null allele in the mouse Krox-20 gene, which encodes a zinc-finger transcription factor, by in-frame insertion of the Escherichia coli lacZ gene, and have shown that hindbrain segmentation is affected in Krox-20-/- embryos. We demonstrate here that Krox-20 is also activated in Schwann cells before the onset of myelination and that its disruption blocks Schwann cells at an early stage in their differentiation, thus preventing myelination in the peripheral nervous system. In Krox-20-/- mice, Schwann cells wrap their cytoplasmic processes only one and a half turns around the axon, and although they express the early myelin marker, myelin-associated glycoprotein, late myelin gene products are absent, including those for protein zero and myelin basic protein. Therefore Krox-20 is likely to control a set of genes required for completion of myelination in the peripheral nervous system.

                Author and article information

                J Cell Biol
                J. Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                17 May 2010
                : 189
                : 4
                : 701-712
                [1 ]Institut für Biochemie, Emil-Fischer-Zentrum and [2 ]Institut für Physiologie und Pathophysiologie, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
                [3 ]Institut für Humananatomie und Embryologie, Universität Regensburg, 93053 Regensburg, Germany
                [4 ]Max-Planck-Institut für Neurobiologie, 82152 Martinsried, Germany
                [5 ]Department of Cell Biology and Genetics, Erasmus Medical Center, 3015 CE Rotterdam, Netherlands
                Author notes
                Correspondence to Michael Wegner: m.wegner@ 123456biochem.uni-erlangen.de
                © 2010 Finzsch et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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