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Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy

BACKGROUND: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the...

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Autores principales: Aranmolate, Azeez, Tse, Nathaniel, Colognato, Holly
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556620/
https://www.ncbi.nlm.nih.gov/pubmed/28806929
http://dx.doi.org/10.1186/s12868-017-0381-0
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author Aranmolate, Azeez
Tse, Nathaniel
Colognato, Holly
author_facet Aranmolate, Azeez
Tse, Nathaniel
Colognato, Holly
author_sort Aranmolate, Azeez
collection PubMed
description BACKGROUND: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the cellular etiology remains poorly understood. We recently found that dystroglycan, a receptor component of the DGC that binds intracellularly to dystrophin, regulates the development of oligodendrocytes, the myelinating glial cells of the brain. RESULTS: We investigated whether dystrophin contributes to oligodendroglial function and brain myelination. We found that oligodendrocytes express up to three dystrophin isoforms, in conjunction with classic DGC components, which are developmentally regulated during differentiation and in response to extracellular matrix engagement. We found that mdx mice, a model of DMD lacking expression of the largest dystrophin isoform, have delayed myelination and inappropriate oligodendrocyte progenitor proliferation in the cerebral cortex. When we prevented the expression of all oligodendroglial dystrophin isoforms in cultured oligodendrocytes using RNA interference, we found that later stages of oligodendrocyte maturation were significantly delayed, similar to mdx phenotypes in the developing brain. CONCLUSIONS: We find that dystrophin is expressed in oligodendrocytes and influences developmental myelination, which provides new insight into potential cellular contributors to brain dysfunction associated with DMD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12868-017-0381-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-55566202017-08-16 Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy Aranmolate, Azeez Tse, Nathaniel Colognato, Holly BMC Neurosci Research Article BACKGROUND: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the cellular etiology remains poorly understood. We recently found that dystroglycan, a receptor component of the DGC that binds intracellularly to dystrophin, regulates the development of oligodendrocytes, the myelinating glial cells of the brain. RESULTS: We investigated whether dystrophin contributes to oligodendroglial function and brain myelination. We found that oligodendrocytes express up to three dystrophin isoforms, in conjunction with classic DGC components, which are developmentally regulated during differentiation and in response to extracellular matrix engagement. We found that mdx mice, a model of DMD lacking expression of the largest dystrophin isoform, have delayed myelination and inappropriate oligodendrocyte progenitor proliferation in the cerebral cortex. When we prevented the expression of all oligodendroglial dystrophin isoforms in cultured oligodendrocytes using RNA interference, we found that later stages of oligodendrocyte maturation were significantly delayed, similar to mdx phenotypes in the developing brain. CONCLUSIONS: We find that dystrophin is expressed in oligodendrocytes and influences developmental myelination, which provides new insight into potential cellular contributors to brain dysfunction associated with DMD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12868-017-0381-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-14 /pmc/articles/PMC5556620/ /pubmed/28806929 http://dx.doi.org/10.1186/s12868-017-0381-0 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Aranmolate, Azeez
Tse, Nathaniel
Colognato, Holly
Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title_full Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title_fullStr Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title_full_unstemmed Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title_short Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy
title_sort myelination is delayed during postnatal brain development in the mdx mouse model of duchenne muscular dystrophy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556620/
https://www.ncbi.nlm.nih.gov/pubmed/28806929
http://dx.doi.org/10.1186/s12868-017-0381-0
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AT colognatoholly myelinationisdelayedduringpostnatalbraindevelopmentinthemdxmousemodelofduchennemusculardystrophy