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The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS
The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669698/ https://www.ncbi.nlm.nih.gov/pubmed/25950478 http://dx.doi.org/10.1038/cddis.2015.119 |
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author | Chung, S-H Biswas, S Selvaraj, V Liu, X-B Sohn, J Jiang, P Chen, C Chmilewsky, F Marzban, H Horiuchi, M Pleasure, D E Deng, W |
author_facet | Chung, S-H Biswas, S Selvaraj, V Liu, X-B Sohn, J Jiang, P Chen, C Chmilewsky, F Marzban, H Horiuchi, M Pleasure, D E Deng, W |
author_sort | Chung, S-H |
collection | PubMed |
description | The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38α MAPK in OL development and myelination in vivo, we generated p38α conditional knockout (CKO) mice under the PLP and nerve/glial antigen 2 (NG2) gene promoters, as these genes are specifically expressed in OL progenitor cells (OPCs). Our data revealed that myelin synthesis was completely inhibited in OLs differentiated from primary OPC cultures derived from the NG2 Cre-p38α CKO mouse brains. Although an in vivo myelination defect was not obvious after gross examination of these mice, electron microscopic analysis showed that the ultrastructure of myelin bundles was severely impaired. Moreover, the onset of myelination in the corpus callosum was delayed in the knockout mice compared with p38α fl/fl control mice. A delay in OL differentiation in the central nervous system was observed with concomitant downregulation in the expression of OPC- and OL-specific genes such as Olig1 and Zfp488 during early postnatal development. OPC proliferation was not affected during this time. These data indicate that p38α is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38α on remyelination in the cuprizone-induced demyelination model. The p38α CKO mice exhibited better remyelination capability compared with p38α fl/fl mice following demyelination. The opposing roles of p38α in myelination and remyelination could be due to a strong anti-inflammatory effect of p38α or a dual reciprocal regulatory action of p38α on myelin formation during development and on remyelination after demyelination. |
format | Online Article Text |
id | pubmed-4669698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46696982015-12-04 The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS Chung, S-H Biswas, S Selvaraj, V Liu, X-B Sohn, J Jiang, P Chen, C Chmilewsky, F Marzban, H Horiuchi, M Pleasure, D E Deng, W Cell Death Dis Original Article The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38α MAPK in OL development and myelination in vivo, we generated p38α conditional knockout (CKO) mice under the PLP and nerve/glial antigen 2 (NG2) gene promoters, as these genes are specifically expressed in OL progenitor cells (OPCs). Our data revealed that myelin synthesis was completely inhibited in OLs differentiated from primary OPC cultures derived from the NG2 Cre-p38α CKO mouse brains. Although an in vivo myelination defect was not obvious after gross examination of these mice, electron microscopic analysis showed that the ultrastructure of myelin bundles was severely impaired. Moreover, the onset of myelination in the corpus callosum was delayed in the knockout mice compared with p38α fl/fl control mice. A delay in OL differentiation in the central nervous system was observed with concomitant downregulation in the expression of OPC- and OL-specific genes such as Olig1 and Zfp488 during early postnatal development. OPC proliferation was not affected during this time. These data indicate that p38α is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38α on remyelination in the cuprizone-induced demyelination model. The p38α CKO mice exhibited better remyelination capability compared with p38α fl/fl mice following demyelination. The opposing roles of p38α in myelination and remyelination could be due to a strong anti-inflammatory effect of p38α or a dual reciprocal regulatory action of p38α on myelin formation during development and on remyelination after demyelination. Nature Publishing Group 2015-05 2015-05-07 /pmc/articles/PMC4669698/ /pubmed/25950478 http://dx.doi.org/10.1038/cddis.2015.119 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Chung, S-H Biswas, S Selvaraj, V Liu, X-B Sohn, J Jiang, P Chen, C Chmilewsky, F Marzban, H Horiuchi, M Pleasure, D E Deng, W The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title | The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title_full | The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title_fullStr | The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title_full_unstemmed | The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title_short | The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS |
title_sort | p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the cns |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669698/ https://www.ncbi.nlm.nih.gov/pubmed/25950478 http://dx.doi.org/10.1038/cddis.2015.119 |
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