MOLECULAR MECHANISMS OF NEURONAL MORPHOGENESIS

神经元形态发生的分子机制

• 批准号: 2379890
• 负责人: LIQUN LUO
• 金额: $ 19.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-25 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2379890
• 关键词: Drosophilidae; afferent nerve; animal genetic material tag; cell cycle proteins; cerebellar Purkinje cell; chimeric proteins; developmental genetics; developmental neurobiology; enzyme activity; enzyme induction /repression; gene mutation; genetically modified animals; intermolecular interaction; laboratory mouse; molecular cloning; neurogenetics; neuronal guidance; protein kinase; site directed mutagenesis

DESCRIPTION: The long-term goal of the research is to understand the molecular mechanism by which neurons acquire their characteristic pattern of connectivity during development. Recent evidence suggests that Rac and Cdc42, members of small GTPase of the Rho subfamily, mediate signaling from extracellular factors to the actin cytoskeleton in the regulation of neuronal arborization. The PI identified a Cdc42-binding protein, C17, in Drosophila. C17 binds to Cdc42 in a GTP-dependent manner and is highly enriched in the nervous system at the time of axonal and dendritic outgrowth. The amino third of C17 shares homology with human myotonic dystrophy protein kinase. In addition, C17 also contains domains suggestive of cytoskeletal association and regulation by other signaling molecules. The c17 mutants display defects in actin cytoskeleton and neuronal function. In this proposal, the role of C17 in the morphogenesis of neurons will be assessed by genetic interaction with other genes required in axon guidance, by biochemical studies of the regulation of its kinase activity, and by subcellular localization studies. In addition, the function of mouse C17 homolog in the morphogenesis of cerebellar Purkinje cells will be analyzed by expressing dominant negative mutants of mouse C17. Knowledge of how neurons generate axons and dendrites in development may help us understand regeneration following nerve injury. The high degree of sequence similarity between C17 and myotonic dystrophy protein kinase suggests functional similarities of the two proteins. Thus understanding the biological function C17 may shed light on the molecular pathogenesis of myotonic dystrophy, the most common adult form of muscular dystrophy.

描述：研究的长期目标是了解 神经元获得其特征模式的分子机制 开发过程中的连通性。 最近的证据表明RAC和 cdc42，小型GTPase的成员Rho亚家族，介导信号传导 调节肌动蛋白细胞骨架的细胞外因子 神经元树木。 PI确定了Cdc42结合蛋白C17， 果蝇。 C17以GTP依赖性方式与Cdc42结合，并且高度 在轴突和树突状时富含神经系统 出生。 C17的氨基三分之一与人体肌发电量共享同源性 营养不良蛋白激酶。 此外，C17还包含域暗示性 其他信号分子的细胞骨架关联和调节。 C17突变体在肌动蛋白细胞骨架和神经元功能中显示缺陷。 在此提案中，C17在神经元形态发生中的作用将是 通过与轴突引导中需要的其他基因的遗传相互作用评估， 通过对其激酶活性调节的生化研究，并通过 亚细胞定位研究。 另外，鼠标C17的功能 将分析小脑Purkinje细胞形态发生的同源物 通过表达小鼠C17的显性阴性突变体。 了解神经元如何在发育中产生轴突和树突的知识可能 帮助我们了解神经损伤后的再生。 高度 C17和肌发育症蛋白激酶之间的序列相似性 建议两种蛋白质的功能相似性。 因此理解 生物函数C17可能会阐明 肌营养不良症，是最常见的成年肌肉营养不良形式。