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An essential role for P38 MAP kinase signalling in oligodendrocyte differentiation
Author(s) -
Bhat N. R.,
Fan F.,
Pawate S.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.81.s1.15_8.x
Subject(s) - mapk/erk pathway , microbiology and biotechnology , myelin basic protein , biology , p38 mitogen activated protein kinases , protein kinase a , kinase , oligodendrocyte , gene isoform , cellular differentiation , myelin , biochemistry , neuroscience , gene , central nervous system
Proliferating oligodendrocyte progenitors (OLPs) cease to divide and undergo differentiation to express myelin‐specific markers and genes upon growth factor withdrawal. We report here that signalling via p38 mitogen‐activated protein kinase (p38 MAPK) pathway plays an essential role in this process. SB203580, a specific inhibitor of p38 MAPK, interferes with the characteristic morphological transformation (i.e. from a simple bi‐/tri‐polar shape to a complex multipolar structure) of OLPs and the expression of oligodendrocyte differentiation‐specific antigenic markers, i.e. O4, O1 and myelin basic protein (MBP). RT–PCR analysis reveals a reduced level of mRNA for MBP and myelin associated glycoprotein (MAG) in the inhibitor‐treated cultures. Switching of OLPs from a growth medium to a mitogen‐free differentiation medium leads to an increased phosphorylation of CREB, a transcription factor implicated in myelin gene expression, in a p38 MAPK‐dependent manner. Kinase assays indicate a differential regulation of the p38 MAPK isoforms i.e. a decline, with time in culture, in the activity of the α isoform from an initial high level present in OLPs, in contrast to increased activity levels of the β isoform in differentiating cells. Enforced activation of p38 MAPK by transfection with activated forms of its upstream kinases i.e. MAPK kinase 6 [MKK6b(E)] and [MKK3b(E)], results in a precocious induction of MBP and MAG mRNAs and a marked stimulation of the activity of an MBP promoter‐reporter which can be blocked by the p38 MAPK inhibitor. The results presented strongly support a prominent role for p38 MAPK pathway in oligodendrocyte differentiation and myelin‐specific gene expression. Acknowledgements: Supported in part by NINDS grant # NS41035‐01.