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

The p38 alpha 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 p38 alpha MAPK in OL development and myelination in vivo, we generated p38 alpha 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 alpha 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 p38 alpha 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 alpha is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38 alpha on remyelination in the cuprizone-induced demyelination model. The p38 alpha CKO mice exhibited better remyelination capability compared with p38 alpha fl/fl mice following demyelination. The opposing roles of p38 alpha in myelination and remyelination could be due to a strong anti-inflammatory effect of p38 alpha or a dual reciprocal regulatory action of p38a on myelin formation during development and on remyelination after demyelination.