The role of mTOR signaling in oligodendrocyte differentiation and CNS myelination

为了了解中枢神经系统中少突胶质细胞的分化和髓鞘的形成，有必要定义 细胞内信号通路调节驱动髓鞘形成的细胞质和核事件。一个数字 许多信号通路参与了中枢神经系统髓鞘形成的过程。双方的合作项目 Macklin和Wood实验室的发起是为了定义mTOR信号在 少突胶质细胞和髓鞘生物学。在过去的几年里，我们的实验室做出了重大贡献 通过这一成功的合作，发现了mTOR及其相关复合体的功能。这个 目前的应用解决了在理解mTOR调节机制方面的一个根本差距 通过调节特定的下游靶点实现少突胶质细胞的分化和髓鞘形成。我们早些时候 研究表明，少突胶质细胞丢失mTOR或Raptor，mTORC1相关蛋白，导致 少突胶质细胞分化和脊髓髓鞘形成的启动缺陷。此外，我们发现， 这些小鼠减少了在成年脊髓中维持的髓鞘厚度。一个重要的 这些研究的优势在于，我们还开始定义不同的mTOR依赖和独立 调节大脑与脊髓发育过程中髓鞘形成的途径。当前的目标是 研究的目的是解决以下基本问题：1)mTOR依赖的机制是什么 调控少突胶质祖细胞向分化少突胶质细胞的转化 转录机制，2)mTOR如何调节特定的细胞骨架变化，以启动 髓鞘形成和髓鞘包裹，以及3)mTORC2和整合素连接的激酶之间的串扰是如何 (ILK)途径调节胼胝体中的髓鞘形成？我们将在这两种啮齿动物身上解决这些问题 和斑马鱼模型通过检验以下假设：1)mTOR促进少突胶质细胞分化 通过抑制骨形态发生通路(BMP)信号和下调转录抑制物，2) MTOR通过调节两个过程中特定的细胞骨架靶点促进髓鞘形成的启动 伸展和轴突包裹；3)Rictor通过促进 Akt473与mTOR和ILK协同磷酸化。

To understand oligodendrocyte differentiation and myelin formation in the CNS, it is essential to define how intracellular signaling pathways regulate the cytoplasmic and nuclear events that drive myelination. A number of signaling pathways have been implicated in driving CNS myelination. The collaborative project between the Macklin and Wood laboratories was initiated to define the function specifically of mTOR signaling in oligodendrocyte and myelin biology. Over the past several years, our laboratories have contributed significant findings on the function of mTOR and its associated complexes through this successful collaboration. The current application addresses a fundamental gap in understanding the mechanisms by which mTOR regulates oligodendrocyte differentiation and myelination through regulating specific downstream targets. Our earlier studies demonstrated that oligodendrocyte loss of mTOR or raptor, the mTORC1-associated protein, results in deficits in oligodendrocyte differentiation and initiation of myelination in the spinal cord. Moreover, we found that these mice have reduced myelin thickness that was sustained in the adult spinal cord. A significant strength of the studies is that we have also begun to define distinct mTOR-dependent and –independent pathways that regulate developmental myelination in the brain versus spinal cord. The goal of the current studies is to address the fundamental questions of 1) what are the mTOR-dependent mechanisms that regulate the conversion of oligodendrocyte progenitors to differentiating oligodendrocytes through regulating transcriptional machinery, 2) how does mTOR regulate specific cytoskeletal changes necessary for initiation of myelination and myelin wrapping, and 3) how does the crosstalk between mTORC2 and integrin-linked kinase (ILK) pathways regulate myelination in the corpus callosum? We will address these questions in both rodent and zebrafish models by testing the following hypotheses: 1) mTOR promotes oligodendrocyte differentiation by suppressing bone morphogenetic pathway (BMP) signaling and down-regulating transcriptional inhibitors, 2) mTOR promotes initiation of myelination through regulating specific cytoskeletal targets during both process extension and axon wrapping, and 3) rictor regulates myelination in the corpus callosum through promoting Akt473 phosphorylation in coordination with both mTOR and ILK.