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.

项目摘要功能神经回路的形成需要新生成的正确迁移神经元，轴突的精确指导到适当的突触后靶标，形成精心制作的树突状乔木和建立突触连接。这些过程取决于在整个开发中重复使用细胞表面受体，以响应细胞外环境中存在的指示。跨膜糖蛋白 Dystroglycan参与神经回路发展的多个方面，包括轴突指导和树突状树木化。该提议的目的是定义特定分子途径在内部功能来调节这些过程。第一个目标测试了多糖果与平面细胞极性（PCP）蛋白CELSR3相互作用的假设调节轴突指导。此目标中提出的实验将定义哪个细胞种群在体内调节轴突指导的功能多样化的功能，确定如何 Dystroglycan和Celsr3在体外和体内相互作用，并研究了多糖的损失如何影响PCP途径激活下游的信号传导。第二个目标将集中在了解多糖糖在调节树突木化中的作用。具体来说，概述的实验将研究树突形态如何影响 dystroglycanopathy，确定多个糖果会功能单元 - 自治性并提供对细胞内信号传导的机械洞察力层面层叠的层流层流层流层流调节树突形态。综上所述，提出的实验将定义在调节神经电路发展的多个方面，并提供了洞察力的洞察力这些过程如何影响影响正常营养不良的突变的个体功能。