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， 细胞内信号传导途径调节驱动髓鞘形成的细胞质和细胞核事件。一些 的信号通路已被牵连在驱动中枢神经系统髓鞘形成。该合作项目与 Macklin和Wood实验室开始定义mTOR信号传导在细胞中的特异性功能。 少突胶质细胞和髓磷脂生物学。在过去的几年里，我们的实验室做出了重大贡献。 通过这次成功的合作，我们对mTOR及其相关复合物的功能进行了研究。的 目前的应用解决了在理解mTOR调节机制方面的一个根本性差距， 少突胶质细胞分化和髓鞘形成通过调节特定的下游靶点。我们早先 研究表明，少突胶质细胞mTOR或raptor（mTORC1相关蛋白）的缺失导致 脊髓中少突胶质细胞分化和髓鞘形成起始的缺陷。此外，我们发现， 这些小鼠的髓鞘厚度减少了，而成年小鼠的髓鞘厚度却持续减少。显著 这些研究的优势在于，我们也开始定义不同的mTOR依赖性和非依赖性 调节大脑和脊髓髓鞘形成的途径。当前的目标 研究的目的是解决以下基本问题：1）什么是mTOR依赖性机制， 通过调节少突胶质细胞祖细胞向分化中的少突胶质细胞的转化， 转录机制，2）mTOR如何调节启动所需的特定细胞骨架变化， 髓鞘形成和髓鞘包裹，以及3）mTORC2和整合素连接激酶之间的串扰如何 (ILK)调节胼胝体髓鞘形成的通路我们将在啮齿类动物和 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途径（BMP）信号传导和下调转录抑制剂，2） mTOR通过调节特定的细胞骨架靶点促进髓鞘形成的启动 rictor通过促进胼胝体的髓鞘形成来调节胼胝体的髓鞘形成 Akt473磷酸化与mTOR和ILK两者协调。

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.