Signal Transduction in Axonal and Neuronal Guidance

轴突和神经元引导中的信号转导

• 批准号: 6677000
• 负责人: YI RAO
• 金额: $ 24.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677000
• 关键词: Xenopus; actins; axon; biological signal transduction; cell migration; chemoattractants; focal adhesion kinase; gene targeting; genetically modified animals; guanosinetriphosphatases; immunoprecipitation; laboratory mouse; laboratory rat; membrane proteins; neuronal guidance; neurons; northern blottings; phosphorylation; receptor; retinal ganglion; tyrosine; western blottings

Revised Abstract: Neuronal migration is abnormal in human fetuses carried by mothers using drugs of abuse, which has been replicated in animal models. The understanding of mechanisms leading to defective neuronal migration requires investigation of mechanisms underlying normal neuronal migration. The secreted guidance cue Slit is a protein important for controlling axon projection and neuronal migration in the mammalian brain. Its axonal targets include axons from dopaminergic neurons in the basal forebrain and the retinal ganglionic cells, whereas its neuronal targets include neuronal precursor cells in the embryonic striatal primordium and those in the subventricular zone in the forebrain. Studies of mechanisms of Slit signaling will further our fundamental understanding of axon guidance and neuronal migration, shed light on the projection of dopaminergic axons and migration of neurons in the striatum, and provide a basis for further studies of the effect of addictive substances on neuronal migration. This application will focus on studying signal transduction mechanisms mediating cellular responses to Slit, a diffusible chemorepellent for projecting axons and migrating neurons. Our preliminary studies have led to a hypothetical signal transduction pathway for Slit. It begins with the binding of Slit to the extracellular part of the transmembrane receptor Roundabout (Robo), which increases the interaction of Robo with intracellular proteins and inactivates Cdc42, a member of the Rho family of small GTPases, and WISH, a regulator of actin polymerization. Slit-Robo interaction is hypothesized to decrease the activity of N-WASP, an activator of the Arp2/3 complex, which initiates actin polymerization. This sequence of activation and inactivation will result in repulsion. We will test the proposed pathway by investigating the biochemical and functional relationship of these molecules.

修订摘要：神经元迁移是异常的母亲进行滥用药物，这已被复制在动物模型中的人类胎儿。理解导致缺陷神经元迁移的机制需要调查正常神经元迁移的机制。 分泌的导向因子Slit是一种重要的蛋白质，用于控制哺乳动物脑中的轴突投射和神经元迁移。其轴突靶点包括基底前脑和视网膜神经节细胞中多巴胺能神经元的轴突，而其神经元靶点包括胚胎纹状体原基中的神经元前体细胞和前脑脑室下区中的神经元前体细胞。对Slit信号转导机制的研究将有助于我们对轴突导向和神经元迁移的基本认识，为多巴胺能轴突在纹状体的投射和神经元迁移提供线索，并为进一步研究成瘾物质对神经元迁移的影响提供基础。 本申请将集中于研究介导细胞对Slit反应的信号转导机制，Slit是一种用于投射轴突和迁移神经元的可扩散化学排斥剂。我们的初步研究已经导致了一个假设的信号转导通路的狭缝。它开始于Slit与跨膜受体Roundabout（Robo）的细胞外部分的结合，这增加了Robo与细胞内蛋白的相互作用并使Cdc 42（小GTP酶的Rho家族的成员）和WISH（肌动蛋白聚合的调节剂）失活。Slit-Robo相互作用被假设为降低N-WASP的活性，N-WASP是Arp 2/3复合物的激活剂，其启动肌动蛋白聚合。这种激活和失活的顺序将导致排斥。我们将通过研究这些分子的生化和功能关系来测试所提出的途径。