The role of dystroglycan in neural circuit development.

项目摘要 功能性神经回路的形成需要新生成的神经元的适当迁移。 神经元，精确指导轴突到适当的突触后靶点， 精细的树突状乔木和突触连接的建立。这些过程取决于 在整个发育过程中细胞表面受体的重复使用， 存在于细胞外环境中的有益线索。跨膜糖蛋白 肌营养不良蛋白聚糖参与神经回路发育的多个方面，包括轴突 引导和树枝状分支。本建议的目的是确定具体的 肌营养不良蛋白聚糖在其中起作用以调节这些过程的分子途径。第一个目标 检验了肌营养不良蛋白聚糖与平面细胞极性（PCP）蛋白Celsr3相互作用的假设 来调节轴突的导向在这一目标中提出的实验将确定哪些细胞 群体肌营养不良蛋白聚糖的功能，以调节轴突的指导，在体内，确定如何 肌营养不良蛋白聚糖和Celsr3在体外和体内相互作用，并研究肌营养不良蛋白聚糖的丢失如何影响细胞的功能。 影响PCP通路激活的下游信号传导。第二个目标将侧重于 了解肌营养不良蛋白聚糖在调节树突状分支中的作用。具体而言是 概述的实验将研究树突状形态如何在模型中受到影响， 抗肌营养不良蛋白聚糖病，确定抗肌营养不良蛋白聚糖是否细胞自主发挥功能，并提供 对肌营养不良蛋白聚糖下游的细胞内信号级联的机械见解， 调节树突形态。总之，拟议的实验将确定以下方面的作用： 肌营养不良蛋白聚糖在调节神经回路发育的多个方面，并提供深入了解 这些过程如何在具有影响正常肌营养不良蛋白聚糖的突变的个体中受到影响 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.