Mechanisms of mTOR-mediated myelin sheath growth

项目总结 在中枢神经系统中，个别少突胶质细胞在不同的细胞上产生不同数量的髓鞘 轴突。支配特定数量的髓鞘如何在某些轴突上产生的潜在机制 仍然是细胞神经生物学中的一个基本问题。最近的研究提供了神经活动的证据 促进脊髓环路中髓鞘的生长，但在 少突胶质细胞将轴突活动诱导的信号转导到选择性髓鞘膜生长 仍然不为人所知。PI3K-Akt-mTOR信号通路是调节这些事件的首选候选信号通路，因为它 两者都能促进髓鞘生长，并能在神经活动时被激活。使用以下组合 斑马鱼幼体的遗传操作和活体细胞成像，该项目试图在此基础上 进一步阐明驱动髓鞘的少突胶质细胞内信号事件的知识 成长。这项拟议的工作包括两个部分：目标1将确定一种新的髓鞘生长调节因子和目标 2和3将测试这是否介导了mTOR和神经活动调节的髓鞘生长。共同努力，这项工作 将在少突胶质细胞内定义一个信号轴，该信号轴介导髓鞘生长以响应神经 活动。

PROJECT SUMMARY In the central nervous system, individual oligodendrocytes produce variable amounts of myelin on different axons. The underlying mechanisms governing how specific amounts of myelin are made on certain axons remains a fundamental question in cellular neurobiology. Recent work has provided evidence that neural activity promotes myelin sheath growth in spinal circuits, yet the signaling mechanisms that function within oligodendrocytes to transduce activity-evoked signaling from axons into selective myelin membrane growth remain unknown. The PI3K-Akt-mTOR signaling pathway is a prime candidate to mediate these events, as it both promotes myelin sheath growth and can be activated in response to neural activity. Using a combination of genetic manipulations and in vivo live-cell imaging of zebrafish larvae, this project seeks to build on this knowledge to further elucidate the intracellular signaling events within oligodendrocytes that drive myelin sheath growth. The proposed work has two parts: Aim 1 will identify a novel regulator of myelin sheath growth and Aims 2 and 3 will test if this mediates mTOR and neural activity-regulated myelin sheath growth. Together, this work will define a signaling axis within oligodendrocytes that mediates myelin sheath growth in response to neural activity.