Signaling pathways regulating oligodendrocyte development and function

 描述(申请人提供)：少突胶质细胞(OL)是中枢神经系统中使轴突髓鞘形成的细胞。OL的发育始于脑室带(VZ)前体细胞，这些前体细胞产生少突胶质前体细胞(OPC)，OPC随后增殖、迁移并分化为成熟的髓鞘OL。这一多步骤的过程需要对细胞内信号的精确调控。这项提案的总体目标是确定影响OL发育不同阶段的合作信号通路。利用小鼠遗传学，我们发现细胞内蛋白酪氨酸磷酸酶Shp2是一种在Ras/MAPK通路中具有积极作用的Rasology基因，是OL多个发育阶段的关键调节因子。具体地说，我们发现改变Shp2磷酸酶活性会影响OPC的产生和OL的髓鞘形成。有趣的是，在Shp2功能下游，我们检测到MAPK和WNT信号的变化。在这里，我们建议验证一种假设，即改变Shp2磷酸酶活性的平衡会导致MAPK和WNT途径激活的变化，从而导致OPC的异常生成和OL的髓鞘形成。在第一个目标中，我们将测试Shp2磷酸酶活性和/或适配器功能(S)是否独立于 磷酸酶活性在OPC/OL中起关键作用，并决定Shp2磷酸酶活性改变引起的OPC和髓鞘异常是否影响动物的行为。在第二个目标中，我们将确定MAPK通路在OL发育过程中Shp2信号的下游依赖和独立的作用。在第三个目标中，我们将确定WNT通路在Shp2 Rasology突变引起的OL异常发育中的作用。这些研究将确定MAPK和WNT信号在Shp2功能改变的OL发育下游的具体作用，并对OL发育过程中多个信号通路之间的复杂关系提供新的理解。

 DESCRIPTION (provided by applicant): Oligodendrocytes (OLs) are the cells that myelinate axons in the central nervous system. OL development begins with ventricular zone (VZ) progenitors that give rise to oligodendrocyte progenitor cells (OPCs), which subsequently proliferate, migrate, and differentiate into mature myelinating OLs. This multistep process requires precise regulation of intracellular signaling. The overall goal of this proposal is to identify cooperating signaling pathways that affect distinct stages of OL development. Using mouse genetics, we found that the intracellular protein tyrosine phosphatase Shp2, a RASopathy gene that has a positive role in the RAS/MAPK pathway, is a key regulator of multiple stages of OL development. Specifically, we found that altering Shp2 phosphatase activity impacts the generation of OPCs and also OL myelination. Interestingly, downstream of Shp2 function, we detect changes in MAPK and WNT signaling. Here we propose to test the hypothesis that altering the balance of Shp2 phosphatase activity results in changes in MAPK and WNT pathway activation that results in abnormal OPC generation and OL myelination. In the first aim, we will test if Shp2 phosphatase activity and/or adaptor function(s), independent of phosphatase activity, are critical in OPC/OLs and determine if the OPC and myelination abnormalities caused by altered Shp2 phosphatase activity impacts animal behaviors. In the second aim, we will identify MAPK pathway dependent and independent roles downstream of Shp2 signaling during OL development. In the third aim, we will identify the role of the WNT pathway in abnormal OL development caused by Shp2 RASopathy mutations. These studies will identify the specific roles of MAPK versus WNT signaling downstream of altered Shp2 function OL development, and provide a new understanding of the complex relationships between multiple signaling pathways during OL development.