Molecular Mechanisms of dendrite development in mammalia

哺乳动物树突发育的分子机制

• 批准号: 7195839
• 负责人: YUH NUNG JAN
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195839
• 关键词: Afferent Neurons; Animals; Axon; Biological Models; Brain; Cerebellum; Consensus Sequence; Cytoplasmic Tail; Defect; Dendrites; Depth; Development; Developmental Process; Dissection; Dominant-Negative Mutation; Drosophila genus; Employee Strikes; Family; Genes; Genetic; Genetic Screening; Goals; Hippocampus (Brain); Homologous Gene; Human; Immunoglobulins; Lead; Ligands; Mammals; Mediating; Molecular; Morphology; Mus; Nervous system structure; Neuraxis; Neurons; Pathology; Pattern; Peripheral Nervous System; Protein Binding Domain; Proteins; Rattus; Role; Signal Transduction Pathway; System; Work; Yeasts; axon growth; axon guidance; base; fly; follow-up; gene cloning; in vivo; insight; interest; knockout gene; loss of function; member; mutant; nervous system disorder; novel; programs; receptor; scale up; success; yeast two hybrid system

DESCRIPTION (provided by applicant): For a nervous system to be wired properly, the axons have to be guided toward the correct targets and the dendrites need to have the correct branching pattern and structural specialization. At present, much less is known about the molecular mechanisms that control dendrite development as compared to those controlling axon guidance. A few years ago, our lab initiated a very fruitful genetic dissection of dendrite development using Drosophila Multiple Dendritic neurons as a model system. This ongoing genetic screen has begun to yield important insights about the molecular basis of dendrite development in Drosophila. Given the striking conservation of many molecular mechanisms that control various developmental processes including axon guidance, it is highly likely that the molecular mechanisms controlling dendrite development is conserved between fly and mammals. Indeed, we already have considerable success in our initial efforts to extend our findings from Drosophila to mammalian CNS. We discovered that mPar3/mPar6 have evolutionarily conserved role in controlling neuronal polarity. Further, we discovered a novel Arborless receptor family that has a specific role in controlling dendritic arborization in both fly and mammals. We propose to carry out in depth phenotypic and molecular studies of the "Key genes" already found and to scale up our effort to systematically identify mammalian functional homologues of the Drosophila genes that are key regulators of various aspects of dendrite development. These Key genes should lead to the identification of evolutionarily conserved "Core programs" that control dendrite development in all animals. Our approach is likely to be fruitful in unraveling the molecular mechanisms that control dendrite development in mammalian CNS. The Core programs identified from this work will contribute to the understanding and eventual treatment of human neurological diseases many of which have pathology in dendrites.

描述（由申请人提供）：为了使神经系统正确连接，轴突必须被引导向正确的目标，树突需要具有正确的分支模式和结构专门化。目前，与控制轴突引导的分子机制相比，人们对控制树突发育的分子机制知之甚少。几年前，我们的实验室使用果蝇多树突神经元作为模型系统，对树突发育进行了非常富有成效的遗传解剖。这种正在进行的遗传筛选已经开始对果蝇树突发育的分子基础产生重要的见解。鉴于控制各种发育过程（包括轴突引导）的许多分子机制的显着保守性，控制树突发育的分子机制很可能在果蝇和哺乳动物之间是保守的。事实上，我们在将我们的发现从果蝇扩展到哺乳动物中枢神经系统的初步努力中已经取得了相当大的成功。我们发现 mPar3/mPar6 在控制神经元极性方面具有进化保守的作用。此外，我们发现了一种新的无枝受体家族，它在控制果蝇和哺乳动物的树突分枝中具有特定的作用。我们建议对已发现的“关键基因”进行深入的表型和分子研究，并加大力度系统地鉴定果蝇基因的哺乳动物功能同源物，这些基因是树突发育各个方面的关键调节因子。这些关键基因应该能够识别进化上保守的“核心程序”，控制所有动物的树突发育。我们的方法可能会在揭示控制哺乳动物中枢神经系统树突发育的分子机制方面取得丰硕成果。这项工作确定的核心计划将有助于理解和最终治疗人类神经系统疾病，其中许多疾病在树突中存在病理学。

项目成果

Differential regulation of dendritic and axonal development by the novel Krüppel-like factor Dar1.

• DOI: 10.1523/jneurosci.6307-10.2011
• 发表时间: 2011-03-02
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ye B;Kim JH;Yang L;McLachlan I;Younger S;Jan LY;Jan YN
• 通讯作者: Jan YN