权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Rho regulator-mediated signaling in interneuron development

中间神经元发育中 Rho 调节器介导的信号传导

基本信息

批准号：
8610366
负责人：
Linda Van Aelst
金额：
$ 47.7万
依托单位：
COLD SPRING HARBOR LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610366
关键词：
Action Potentials Address Adolescent Adult Affect Awareness Axon Binding Biochemical Biochemical Genetics Brain Brain Diseases Brain Part Cells Cerebral cortex Complex DOCK1 protein Data Defect Development Diffuse Disease Electrophysiology (science)Elements Embryo Epilepsy Equilibrium ErbB4 gene Family member Gene Expression Genetic Glutamates Goals Guanosine Triphosphate Phosphohydrolases In Situ Interneurons Knowledge Label Laboratories Lead Light Link Mediating Mental disorders Methodology Methods Modeling Molecular Molecular Genetics Morphogenesis Morphology Motor Mus Nervous System Physiology Neurons Neurotransmitters Output Pathway interactions Physiological Physiology Play Population Presynaptic Terminals Property Proteins Receptor Protein-Tyrosine Kinases Regulation Regulatory Element Role Schizophrenia Sensory Process Signal Pathway Signal Transduction Structure Synapses Testing United States base excitatory neuron gamma-Aminobutyric Acid hippocampal pyramidal neuron innovation insight nervous system disorder neuron development novel novel therapeutics prevent protein expression public health relevance receptor rho rho GTP-Binding Proteins tool

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this application is to define the molecular mechanisms that govern the morphological differentiation and functional maturation of a unique class of inhibitory GABAergic interneurons, called chandelier cells (ChCs). These cells are typified by their distinctive axonal morphology with arrays of boutons termed cartridges, and play a central role in maintaining proper nervous system function. Significantly, ChC morphological and functional perturbations are found in common brain disorders, including epilepsy and schizophrenia. Despite the importance of these cells, the molecular mechanisms that regulate ChC morphogenesis remain largely unknown. Our studies initiated to gain insight into the role of Rho regulators in GABAergic interneurons revealed a critical role for the DOCK180 family member DOCK7/Zir2, an activator of Rac, in the morphological differentiation of ChCs. This was made possible by implementing an innovative method that enables genetic labeling and manipulation of single ChCs in situ in developing mouse embryos. Furthermore, we recently found that DOCK7 forms a complex with the schizophrenia-linked ErbB4 tyrosine kinase receptor, which notably the only other protein is so far shown to affect ChC morphogenesis. These findings provide a unique entry point for studies of the molecular basis of ChC morphogenesis and function. This application aims to further define the role of DOCK7 in ChCs, and in particular to identify the molecular pathways DOCK7 is integral to. Towards these goals, the first aim will test the hypothesis that altered DOCK7 expression impacts not only the morphology but also the physiological properties of ChCs. Specifically, we will manipulate DOCK7 levels in a large population of ChCs visualized via GFP marker protein expression in a genetically modified mouse line, which will permit electrophysiology studies of these cells. Aim 2 focuses on the regulation of DOCK7 in ChCs. We conjecture that DOCK7 acts as downstream effectors of ErbB4 to control ChC morphogenesis and function. We will test this hypothesis using molecular, biochemical and genetic approaches and will further define DOCK7 regulatory elements important for this interaction and for DOCK7 function in ChCs. Finally, aim 3 scrutinizes molecular mechanisms downstream of DOCK7 in ChCs. Our preliminary data imply that both Rac-dependent and Rac-independent pathways are involved in mediating DOCK7's effects in ChCs. Hence, we will strive to characterize the Rac-mediated signaling pathways involved and identify novel molecular interactions that mediate DOCK7 function using innovative genetic and molecular approaches. The proposed studies will provide first/vital information on the molecular mechanisms governing ChC differentiation and function. As such, they could shed novel light onto the signaling defects that underlie neurological and mental disorders, such as epilepsy and schizophrenia.

描述（由申请人提供）：本申请的长期目标是定义控制一种独特的抑制性gaba能中间神经元的形态分化和功能成熟的分子机制，称为吊灯细胞（ChCs）。这些细胞的典型特征是它们独特的轴突形态，它们的钮扣排列被称为墨盒，