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Previous <jats:italic>in vitro<\/jats:italic> studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38<jats:italic>\u03b1<\/jats:italic> MAPK in OL development and myelination <jats:italic>in vivo<\/jats:italic>, we generated p38<jats:italic>\u03b1<\/jats:italic> 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-p38<jats:italic>\u03b1<\/jats:italic> CKO mouse brains. Although an <jats:italic>in vivo<\/jats:italic> 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 p38<jats:italic>\u03b1<\/jats:italic> 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 p38<jats:italic>\u03b1<\/jats:italic> is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38<jats:italic>\u03b1<\/jats:italic> on remyelination in the cuprizone-induced demyelination model. The p38<jats:italic>\u03b1<\/jats:italic> CKO mice exhibited better remyelination capability compared with p38<jats:italic>\u03b1<\/jats:italic> fl\/fl mice following demyelination. The opposing roles of p38<jats:italic>\u03b1<\/jats:italic> in myelination and remyelination could be due to a strong anti-inflammatory effect of p38<jats:italic>\u03b1<\/jats:italic> or a dual reciprocal regulatory action of p38<jats:italic>\u03b1<\/jats:italic> on myelin formation during development and on remyelination after demyelination.<\/jats:p>","DOI":"10.1038\/cddis.2015.119","type":"journal-article","created":{"date-parts":[[2015,5,7]],"date-time":"2015-05-07T09:02:17Z","timestamp":1430989337000},"page":"e1748-e1748","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["The p38\u03b1 mitogen-activated protein kinase is a key regulator of myelination and remyelination in the CNS"],"prefix":"10.1038","volume":"6","author":[{"given":"S-H","family":"Chung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Selvaraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X-B","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Sohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Chmilewsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Marzban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Horiuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D E","family":"Pleasure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,5,7]]},"reference":[{"key":"BFcddis2015119_CR1","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1093\/brain\/awl075","volume":"129","author":"R Gold","year":"2006","unstructured":"Gold R, Linington C, Lassmann H . 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