The role of dystroglycan in neural circuit development.

项目摘要 功能神经回路的形成需要新产生的神经元的适当迁移 神经元，精确引导轴突到适当的突触后靶点，形成 精细的树枝和突触连接的建立。这些过程依赖于 关于细胞表面受体在整个发育过程中的重复使用 细胞外环境中存在的指导性线索。跨膜糖蛋白 营养不良多糖参与神经回路发育的多个方面，包括轴突 引导和树枝分枝。这项提案的目标是界定具体的 抗肌营养不良蛋白聚糖调节这些过程的分子途径。第一个目标 测试营养不良糖链与平面细胞极性(PCP)蛋白Celsr3相互作用的假设 来调节轴突引导。在这个目标中提出的实验将定义哪个细胞 人群营养不良多糖在体内调节轴突引导的功能，决定如何 抗肌营养不良多糖和Celsr3在体外和体内相互作用，并研究肌营养不良聚糖的丢失如何 影响PCP通路激活的信号下游。第二个目标将集中在 了解营养不良多糖在调节树突分枝中的作用。具体地说， 概述的实验将检查树突形态如何在模型中受到影响 营养不良糖链病，确定营养不良糖链是否自主发挥细胞功能并提供 对营养不良多糖下游细胞内信号级联的机械性洞察 调节树枝状形态。综上所述，拟议的实验将定义 营养不良葡聚糖在调节神经回路发育的多个方面的作用 这些过程是如何在具有影响正常营养不良的突变的个体中受到影响的 功能。

Project Summary The formation of functional neural circuits requires the proper migration of newly generated neurons, precise guidance of axons to the appropriate postsynaptic targets, the formation of elaborate dendritic arbors and establishment of synaptic connections. These processes depend on the reiterative use of cell-surface receptors throughout development that respond to instructive cues present in the extracellular environment. The transmembrane glycoprotein dystroglycan is involved in multiple aspects of neural circuit development, including axon guidance and dendritic arborization. The objective of this proposal is to define the specific molecular pathways that dystroglycan functions within to regulate these processes. The first aim tests the hypothesis that dystroglycan interacts with the planar cell polarity (PCP) protein Celsr3 to regulate axon guidance. The experiments proposed in this aim will define which cellular populations dystroglycan functions in to regulate axon guidance in vivo, determine how dystroglycan and Celsr3 interact in vitro and in vivo and investigate how the loss of dystroglycan affects signaling downstream of PCP pathway activation. The second aim will focus on understanding the role of dystroglycan in regulating dendritic arborization. Specifically, the experiments outlined will examine how dendritic morphology is affected in models of dystroglycanopathy, determine if dystroglycan functions cell-autonomously and provide mechanistic insight into the intracellular signaling cascades downstream of dystroglycan that regulate dendritic morphology. Taken together, the proposed experiments will define the role of dystroglycan in regulating multiple aspects of neural circuit development and provide insight into how these processes are affected in individuals with mutations that affect normal dystroglycan function.