The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS

S. H. Chung, S. Biswas, V. Selvaraj, X. B. Liu, J. Sohn, P. Jiang, C. Chen, F. Chmilewsky, H. Marzban, M. Horiuchi, David E Pleasure, Wenbin Deng

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Abstract

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 OLspecific 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.

Original languageEnglish (US)
Article numbere1748
JournalCell Death and Disease
Volume6
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Oligodendroglia
p38 Mitogen-Activated Protein Kinases
Knockout Mice
Demyelinating Diseases
Stem Cells
Myelin Sheath
Neuroglia
Cuprizone
Genes
Biological Phenomena
Antigens
Corpus Callosum
Protein-Serine-Threonine Kinases
Cell Movement
Cell Differentiation
Anti-Inflammatory Agents
Down-Regulation
Central Nervous System
Cell Culture Techniques
Cell Proliferation

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

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, David E; Deng, Wenbin.

In: Cell Death and Disease, Vol. 6, No. 5, e1748, 01.05.2015.

Research output: Contribution to journalArticle

Chung, SH, Biswas, S, Selvaraj, V, Liu, XB, Sohn, J, Jiang, P, Chen, C, Chmilewsky, F, Marzban, H, Horiuchi, M, Pleasure, DE & Deng, W 2015, 'The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS', Cell Death and Disease, vol. 6, no. 5, e1748. https://doi.org/10.1038/cddis.2015.119
Chung, S. H. ; Biswas, S. ; Selvaraj, V. ; Liu, X. B. ; Sohn, J. ; Jiang, P. ; Chen, C. ; Chmilewsky, F. ; Marzban, H. ; Horiuchi, M. ; Pleasure, David E ; Deng, Wenbin. / The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS. In: Cell Death and Disease. 2015 ; Vol. 6, No. 5.
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abstract = "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 OLspecific 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.",
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AU - Jiang, P.

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AB - 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 OLspecific 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.

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