The role of dystroglycan in neural circuit development.

肌营养不良聚糖在神经回路发育中的作用。

基本信息

批准号：
9979988
负责人：
Kevin Wright
金额：
$ 33.69万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979988
关键词：
Affect Alleles Axon Binding Biochemical Cell Surface Receptors Cell physiology Cues Cytoskeleton Defect Development Dystroglycan Environment Extracellular Matrix Extracellular Protein Genes Genetic Genetic Screening Glycoproteins Human In Vitro Individual Instruction Integral Membrane Protein Lead Ligand Binding Link Modeling Molecular Morphology Mus Mutant Strains Mice Mutation Nervous system structure Neurodevelopmental Disorder Neurons Pathway interactions Pattern Population Process Prosencephalon Proteins Regulation Role Series Signal Pathway Signal Transduction Spinal Cord Synapses System Testing axon guidance congenital muscular dystrophy dystroglycanopathy experimental study extracellular glycosylation glycosyltransferase human model in vivo insight migration mild cognitive impairment mouse model mutant neural circuit neurodevelopment novel planar cell polarity postsynaptic synaptogenesis

项目摘要

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.

项目概要功能性神经回路的形成需要新生成的神经回路的适当迁移神经元，轴突精确引导到适当的突触后目标，形成精心设计的树突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重复使用细胞表面受体来响应细胞外环境中存在的指导性线索。跨膜糖蛋白肌营养不良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树枝化。该提案的目的是确定具体的肌营养不良聚糖发挥作用以调节这些过程的分子途径。第一个目标检验肌营养不良聚糖与平面细胞极性 (PCP) 蛋白 Celsr3 相互作用的假设调节轴突引导。该目标中提出的实验将定义哪种细胞群体肌营养不良聚糖的功能是调节体内轴突引导，确定如何肌营养不良聚糖和 Celsr3 在体外和体内相互作用，并研究肌营养不良聚糖如何丢失影响 PCP 通路激活下游的信号传导。第二个目标将集中于了解肌营养不良聚糖在调节树突分枝中的作用。具体来说，概述的实验将检查树突形态在模型中如何受到影响肌营养不良症，确定肌营养不良聚糖是否具有细胞自主功能并提供对肌营养不良聚糖下游细胞内信号级联的机制洞察调节树突形态。总而言之，拟议的实验将定义肌营养不良聚糖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聚糖的突变的个体中受到影响功能。