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

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

doi:10.1038/cddis.2015.119

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.

Highlights

Myelination is a complicated process involving generation of OL progenitor cells (OPCs), differentiation of OPCs into myelinating OLs, ensheathment of axons by OLs and wrapping the nerves with the expansion of myelin sheath.[4,5,6] The study of intracellular signals that regulate myelinogenesis is crucial to our understanding of the developmental and pathological processes in white matter structures
Our data showed that p38 α is a positive regulator of OL development and myelination during central nervous system (CNS) development as both myelination and OL development were impaired in specific forebrain regions of the conditional knockout (CKO) mice
The targeted disruption of the p38α gene in NG2cre/p38α− / − or Plpcrep38α− / − (p38α CKO) mice was mediated by Cre-loxP recombination under the control of the nerve/glial antigen 2 (NG2) or the Plp promoter

Summary

Introduction

Myelination is a complicated process involving generation of OL progenitor cells (OPCs), differentiation of OPCs into myelinating OLs, ensheathment of axons by OLs and wrapping the nerves with the expansion of myelin sheath.[4,5,6] The study of intracellular signals that regulate myelinogenesis is crucial to our understanding of the developmental and pathological processes in white matter structures. The p38 MAPK family members (p38α, p38β, p38γ and p38δ) in particular are implicated in various biological processes, such as cell survival, proliferation and differentiation.[7,8,9,10] The p38α is well established as a mediator of stress responses in neural cells; its physiological role(s) during OL development and myelination has only been recognized recently.[11,12,13,14,15,16] Using p38 inhibitors, several studies have demonstrated that p38α MAPK is important for myelination in cultured Schwann cells[11]. In an effort to identify the specific role(s) of p38α in myelination during early postnatal development, we have bred p38α-floxed (p38α fl/fl) mice with nerve/glial antigen 2 (NG2) or proteolipid peptide (PLP)-cre mice to generate homozygous conditional NG2/Plp-specific p38α knockout mice for the first time. Our findings identified novel reciprocal roles of p38α during OL development in the early postnatal brain and during remyelination in adult mice, implicating the therapeutic potential of p38α inhibition in CNS remyelination

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Conclusion