YAP/TAZ对外周神经系统内髓鞘形成的作用及调控机制

Myelin is a multilayered membrane sheath that wraps axons and provides electrical insulation and low-capacitance ensheathment of axons for rapid impulse conduction in vertebrate nervous system. The integrity of myelin is essential, as emphasized by frequent neurological diseases caused by malformation or deterioration of the myelin sheath, including multiple sclerosis, leukodystrophies and peripheral neuropathies. Myelination is affected by a series of signaling pathways and transcription factors that together regulate the process. YAP/TAZ are downstream effectors of hippo signaling pathway found in recent years, and many studies have reported that YAP/TAZ involved in Tumorigenesis and metastasis of human. However, the role of YAP/TAZ in myelination and nerve development is still unclear. In this study, we intend to evaluate the effect of YAP/TAZ on myelination and explore the mechanisms how YAP/TAZ promote schwann cell differentiation by using conditional knockout mouse model and in vitro primary cell culture model. This study can improve our understanding of the development of the nervous system and probably find meaningful therapeutic targets for dysmyelinating and demyelinating diseases.

髓鞘是包裹在脊椎动物神经元轴突外的一种绝缘膜结构，它能阻止电信号透过轴突细胞膜，从而加速神经信号的传递。髓鞘的完整性是必要的，髓鞘发育不良或髓鞘异常脱落会引起机体发生一系列神经系统疾病，如多发性硬发症、脑白质营养不良和周围神经病变等。髓鞘形成过程受一系列信号通路及转录因子的正负协同调控。YAP/TAZ是近年发现的Hippo信号通路的转录效应因子，许多研究报道YAP/TAZ参与人类肿瘤的发生与转移，然而 YAP/TAZ在髓鞘形成及神经发育过程中的作用目前仍不清楚。本研究拟采用条件性敲除小鼠模型和体外原代细胞培养模型，研究YAP/TAZ对髓鞘形成的影响及可能的分子机制。该项目可以提高我们对于神经系统发育的认识，并可能发现针对髓鞘形成不良及脱髓鞘疾病有意义的治疗靶点。

周围神经系统中的施旺氏细胞髓鞘化对于运动功能是必需的，髓鞘发育不良或异常脱落会引起机体发生一系列周围神经病变。近年发现的参与调控细胞增殖与分化的Hippo信号通路转录效应因子YAP/TAZ，对髓鞘形成及神经发育的调控作用尚不清楚。在该项目中，我们使用条件性敲除小鼠模型和体外原代细胞培养模型，研究YAP/TAZ在施旺氏细胞发育及髓鞘形成中的功能，并探讨可能分子机制。经研究发现YAP/TAZ 对于施旺氏细胞增殖和分化起双重调控作用，是一个阶段依赖性的关键因子，其作用具剂量依赖性。全基因组占据图谱和转录组分析揭示YAP/TAZ通过激活细胞周期调节因子促进SC增殖，同时结合SOX10激活关键分化调节剂，促进髓鞘形成。我们进一步确定TAZ靶向抑制G蛋白Gαs编码基因Gnas表达，Gαs拮抗TAZ / YAP，减缓SC扩增。Gnas缺失扩大SC前体池并阻断外周髓鞘形成。因此，Hippo / TAZ / YAP和Gαs-蛋白反馈回路作为平衡SC增殖和分化的支点，为SC谱系发育进展和体内平衡的分子编程提供见解。