Signaling pathways regulating oligodendrocyte development and function

调节少突胶质细胞发育和功能的信号通路

• 批准号: 8886021
• 负责人: RONALD R WACLAW
• 金额: $ 34.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886021
• 关键词: Affect; Alleles; Animal Behavior; Axon; Brain; Brain region; CSPG4 gene; Cell Differentiation process; Cells; Complex; Data; Defect; Development; Dominant-Negative Mutation; Embryo; Equilibrium; Exhibits; Functional disorder; Gastrointestinal tract structure; Gene Expression; Generations; Genes; Genetic; Genome; Goals; Human; LEOPARD Syndrome; Label; Learning Disabilities; MAP Kinase Gene; MAP2K1 gene; MEKs; Mus; Mutate; Mutation; Neuraxis; Neurocognitive Deficit; Noonan Syndrome; Oligodendroglia; PTPN11 gene; Paper; Pathway interactions; Patients; Peripheral Nervous System; Phase; Phenotype; Phosphoric Monoester Hydrolases; Physiological; Process; Proliferating; Protein Tyrosine Phosphatase; RNA; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Syndrome; Testing; Time; Ventricular; WNT Signaling Pathway; base; cell type; gain of function; improved; migration; mutant; myelination; oligodendrocyte lineage; oligodendrocyte myelination; progenitor; public health relevance; white matter

 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.

 描述（由申请人提供）：少突胶质细胞（OL）是中枢神经系统中使轴突有髓鞘的细胞。 OL 的发育始于心室区 (VZ) 祖细胞，产生少突胶质祖细胞 (OPC)，随后增殖、迁移并分化为成熟的有髓鞘 OL。这个多步骤过程需要精确调节细胞内信号传导。该提案的总体目标是确定影响 OL 发育不同阶段的协同信号通路。利用小鼠遗传学，我们发现细胞内蛋白酪氨酸磷酸酶 Shp2（一种在 RAS/MAPK 通路中发挥积极作用的 RAS 病基因）是 OL 发育多个阶段的关键调节因子。具体来说，我们发现改变 Shp2 磷酸酶活性会影响 OPC 的生成以及 OL 髓鞘形成。有趣的是，在 Shp2 功能的下游，我们检测到 MAPK 和 WNT 信号传导的变化。在这里，我们建议检验以下假设：改变 Shp2 磷酸酶活性的平衡会导致 MAPK 和 WNT 通路激活的变化，从而导致 OPC 生成和 OL 髓鞘形成异常。在第一个目标中，我们将测试 Shp2 磷酸酶活性和/或接头功能是否独立于 磷酸酶活性，对于 OPC/OL 至关重要，并确定由 Shp2 磷酸酶活性改变引起的 OPC 和髓鞘形成异常是否会影响动物行为。在第二个目标中，我们将确定 OL 发育过程中 Shp2 信号下游的 MAPK 通路依赖和独立作用。第三个目标是确定 WNT 通路在 Shp2 RASopathy 突变引起的 OL 异常发育中的作用。这些研究将确定 MAPK 与 WNT 信号下游在改变的 Shp2 功能 OL 发育中的具体作用，并为 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。