title: The p38α mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS.
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 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.
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA [2] Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: S-H
authors.initials: SH
authors.lastname: Chung
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
authors.forename: S
authors.initials: S
authors.lastname: Biswas
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA [2] Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: V
authors.initials: V
authors.lastname: Selvaraj
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
authors.forename: X-B
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sohn
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Oral Biology, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: F
authors.initials: F
authors.lastname: Chmilewsky
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Marzban
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
authors.forename: M
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Pleasure
authors.affiliation: 1] Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA [2] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA [3] Medical College, Hubei University of Arts and Science, Xiangyang, Hubei 441053, China.
authors.forename: W
authors.initials: W
authors.lastname: Deng
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology; D003711:Demyelinating Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology
chemical_list: D048308:Mitogen-Activated Protein Kinase 14