Oligodendrocytes (OLs) myelinate axons and provide electrical insulation and trophic support for neurons in the central nervous system (CNS). Platelet-derived growth factor (PDGF) is critical for steady-state number and differentiation of oligodendrocyte precursor cells (OPCs), but its downstream targets are unclear. Here, we show for the first time that Gab1, an adaptor protein of receptor tyrosine kinase, is specifically expressed in OL lineage cells and is an essential effector of PDGF signaling in OPCs in mice. Gab1 is down-regulated by PDGF stimulation and up-regulated during OPC differentiation. Conditional deletions of Gab1 in OLs cause CNS hypomyelination by affecting OPC differentiation. Moreover, Gab1 binds to downstream GSK3β and regulated its activity, and thereby affects the nuclear accumulation of β-catenin and the expression of a number of transcription factors critical to myelination. Our work uncovers a novel downstream target of PDGF signaling, which is essential to OPC differentiation and CNS myelination.

中文翻译：

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Gab1介导PDGF信号传导，对少突胶质细胞分化和中枢神经系统髓鞘形成至关重要

少突胶质细胞（OLs）产生髓鞘轴突，并为中枢神经系统（CNS）的神经元提供电绝缘和营养支持。血小板衍生生长因子（PDGF）对于少突胶质前体细胞（OPC）的稳态数目和分化至关重要，但尚不清楚其下游靶点。在这里，我们首次展示了受体酪氨酸激酶的衔接蛋白Gab1在OL谱系细胞中特异性表达，并且是小鼠OPC中PDGF信号传导的重要效应子。Gab1受PDGF刺激下调，在OPC分化过程中上调。Gab1的条件删除OLs中的TNFα通过影响OPC分化而引起CNS髓鞘减少。此外，Gab1与下游GSK3β结合并调节其活性，从而影响β-catenin的核蓄积和许多对髓鞘形成至关重要的转录因子的表达。我们的工作发现了PDGF信号传导的新型下游靶标，这对OPC分化和CNS髓鞘化至关重要。