Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase.
Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase.
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DOI：
10.1523/jneurosci.2546-10.2010
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发表时间：
2010-08-18
期刊：
影响因子：
--
通讯作者：
Gallo V
中科院分区：
文献类型：
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作者：
Chew LJ;Coley W;Cheng Y;Gallo V
许多细胞外和内在因素调节少突胶质细胞的发育，但其信号通路仍然知之甚少。虽然p38丝裂原活化蛋白激酶（MAPK）依赖性途径与少突胶质细胞祖细胞（OPC）谱系进展有关，但其参与髓鞘形成的分子靶点在很大程度上尚未确定。我们已经分析了p38 MAPK调节少突胶质细胞发育的机制，并证明p38 MAPK抑制可阻止OPC谱系进展，并抑制MBP启动子活性和Sox 10功能。在白色组织中，在少突胶质细胞谱系细胞中观察到不同水平的MAPK磷酸化。磷酸化p38 MAPK被发现在CC 1和CNP表达分化的少突胶质细胞的成年大脑，并暂时与磷酸化ERK水平的下降，在这个谱系的细胞。PDGF刺激ERK、p38 MAPK和JNK的磷酸化，并且p38 MAPK抑制与ERK、JNK和c-Jun磷酸化增加相关。在PDGF的存在下，同时抑制p38 MAPK和MEK或JNK显著地增强了单独抑制p38 MAPK诱导的髓鞘基因表达和谱系进展的抑制。显性失活的c-Jun可逆转活性MEK 1或显性失活的p38 MAPK α突变体对髓鞘启动子活性的抑制作用，并且在p38 MAPK抑制后，在MBP启动子处检测到磷酸化的c-Jun，表明c-Jun是p38 MAPK作用的负介导物。我们的研究结果表明，p38 MAPK活性在大脑中支持髓鞘基因的表达，通过不同的机制，通过积极和消极的调控目标。我们发现，少突胶质细胞分化涉及p38介导的Sox 10调节和串扰与平行的ERK和JNK途径抑制c-Jun活性。
Many extracellular and intrinsic factors regulate oligodendrocyte development, but their signaling pathways remain poorly understood. While 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 largely unidentified. We have analyzed mechanisms by which p38MAPK regulates oligodendrocyte development and demonstrate that p38MAPK inhibition prevents OPC lineage progression, and inhibits MBP 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 ERK in cells of this lineage. PDGF stimulates the phosphorylation of ERK, p38MAPK and 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 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 p38MAPKα mutants, and phosphorylated c-Jun was detected at the MBP promoter following p38MAPK inhibition, indicating c-Jun as a negative mediator of p38MAPK action. Our findings indicate that p38MAPK activity in the brain supports myelin gene expression through distinct mechanisms via positive and negative regulatory targets. We show that oligodendrocyte differentiation involves p38-mediated Sox10 regulation and crosstalk with parallel ERK and JNK pathways to repress c-Jun activity.