Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation.
Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation.
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DOI：
10.1523/jneurosci.0234-09.2009
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发表时间：
2009-05-13
期刊：
影响因子：
--
通讯作者：
Wood TL
中科院分区：
文献类型：
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作者：
Tyler WA;Gangoli N;Gokina P;Kim HA;Covey M;Levison SW;Wood TL
虽然外在和内在的因素已经确定，编排的分化和成熟的少突胶质细胞，较少的是已知的细胞内信号通路，控制整体承诺分化。在这里，我们提供的证据表明，雷帕霉素（mTOR）的哺乳动物靶的激活是少突胶质细胞分化所必需的。具体地，mTOR调节在晚期祖细胞向未成熟少突胶质细胞转变时的少突胶质细胞分化，如通过阶段特异性抗原和髓鞘蛋白（包括MBP和PLP）的表达所评估的。此外，丝氨酸2448上mTOR的磷酸化与发育中大脑皮质下白色物质中的髓鞘形成相关。我们证明，mTOR通过两种不同的信号复合物，mTORC 1和mTORC 2，定义的衔接蛋白raptor和rictor的存在下，分别发挥其对少突胶质细胞分化的影响。通过siRNA介导的raptor或rictor的敲低破坏mTOR复合物形成显著降低了体外髓鞘蛋白表达。然而，mTORC 2单独控制髓鞘基因的表达在mRNA水平上，而mTORC 1通过另一种机制影响MBP的表达。此外，对mTORC 1和mTORC 2靶点的研究揭示了少突胶质细胞分化过程中的差异磷酸化。在OPC-DRG共培养物中，抑制mTOR有效地消除了少突胶质细胞分化并减少了髓鞘片段的数量。这些数据支持mTOR在髓鞘形成之前调节少突胶质细胞分化的承诺的假设。
While both extrinsic and intrinsic factors have been identified that orchestrate the differentiation and maturation of oligodendrocytes, less is known about the intracellular signaling pathways that control the overall commitment to differentiate. Here, we provide evidence that activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. Specifically, mTOR regulates oligodendrocyte differentiation at the late progenitor to immature oligodendrocyte transition as assessed by the expression of stage specific antigens and myelin proteins including MBP and PLP. Furthermore, phosphorylation of mTOR on Ser 2448 correlates with myelination in the subcortical white matter of the developing brain. We demonstrate that mTOR exerts its effects on oligodendrocyte differentiation through two distinct signaling complexes, mTORC1 and mTORC2, defined by the presence of the adaptor proteins raptor and rictor, respectively. Disrupting mTOR complex formation via siRNA mediated knockdown of raptor or rictor significantly reduced myelin protein expression in vitro. However, mTORC2 alone controlled myelin gene expression at the mRNA level, while mTORC1 influenced MBP expression via an alternative mechanism. In addition, investigation of mTORC1 and mTORC2 targets revealed differential phosphorylation during oligodendrocyte differentiation. In OPC-DRG co-cutures, inhibiting mTOR potently abrogated oligodendrocyte differentiation and reduced numbers of myelin segments. These data support the hypothesis that mTOR regulates commitment to oligodendrocyte differentiation prior to myelination.