Mechanisms of Regulation of Oligodendrocyte Development by p38 Mitogen-Activated Protein Kinase

作者：Li‐Jin Chew, William Coley, Ying Cheng, Vittorio Gallo · 发表于：Journal of Neuroscience · 年份：2010 · DOI：10.1523/jneurosci.2546-10.2010 · 被引用次数：91 · 研究领域：Neurogenesis and neuroplasticity mechanisms、MicroRNA in disease regulation、Chromatin Remodeling and Cancer

Many extracellular and intrinsic factors regulate oligodendrocyte development, but their signaling pathways remain poorly understood. Although the p38 mitogen-activated protein kinase (MAPK)-dependent pathway is implicated in oligodendrocyte progenitor cell (OPC) lineage progression, its molecular targets involved in myelinogenesis are mostly unidentified. We have analyzed mechanisms by which p38MAPK regulates oligodendrocyte development and demonstrate that p38MAPK inhibition prevents OPC lineage progression and inhibits MBP (myelin basic protein) promoter activity and Sox10 function. In white-matter tissue, differential levels of MAPK phosphorylation are observed in oligodendrocyte lineage cells. Phosphorylated p38MAPK was found in CC1- and CNP-expressing differentiated oligodendrocytes of the adult brain and was temporally associated with a decline in the levels of phosphorylated extracellular signal-regulated kinase (ERK) in cells of this lineage. PDGF stimulates the phosphorylation of ERK, p38MAPK, and c-Jun N-terminal kinase (JNK), and p38MAPK inhibition was associated with increased ERK, JNK, and c-Jun phosphorylation. In the presence of PDGF, simultaneous inhibition of p38MAPK and either MAPK kinase (MEK) or JNK significantly alleviates the repression of myelin gene expression and lineage progression induced by p38MAPK inhibition alone. Dominant-negative c-Jun reverses the inhibition of myelin promoter activity by active MEK1 or dominant-negative p38MAPKalpha mutants,...