GENETIC AND MOLECULAR STUDIES OF NEUROGENESIS

神经发生的遗传学和分子研究

• 批准号: 6520866
• 负责人: Chris Q Doe
• 金额: $ 47.92万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6520866
• 关键词: DNA binding protein; Drosophilidae; alleles; biochemical evolution; cell type; central nervous system; developmental genetics; developmental neurobiology; gene expression; gene mutation; genetic mapping; genetic regulation; homeobox genes; laboratory mouse; molecular cloning; neurogenesis; neurogenetics; regulatory gene

DESCRIPTION(Applicant's abstract reproduced verbatim): The mammalian CNS contains many different types of neurons and glia, and each plays a specific role in regulating movement, perception, cognition, and overall behavior. It is clinically important to understand how different neural cell types are generated, because it may help us recognize the primary defect in neuro-degenerative diseases, cancers of the nervous system, or behavioral disorders. Defining the molecular/genetic basis of a neural disorder is vital for developing appropriate therapeutic interventions. We are using Drosophila as a model system for understanding how neural diversity is generated. Recent work has shown that Drosophila and mammals share a surprising degree of conservation in the mechanisms regulating neurogenesis. Thus, Drosophila research is an efficient means for uncovering clinically relevant genes. The three specific aims of the research proposed here are to: (1) Identify and characterize genes that establish different neural cell types along the dorsoventral axis of the CNS. Mammalian motoneurons, interneurons, and sensory neurons develop from distinct regions along the dorsoventral axis of the CNS. In Drosophila, there are also differences in the neural cell types along the dorsoventral axis, but very little is known about the mechanisms used to generate these distinct neural fates. (2) Identify and characterize genes that establish different neural cell types produced by individual stem cells. In mammals, a single cerebral cortical stem cell can generate neurons with distinct laminar fates; in Drosophila, a single neural stem cell (neuroblast) also generates a characteristic lineage of neurons and glia with diverse morphology and function within the CNS. We would like to understand how one stem cell can produce multiple, neuronal and glial cell types. (3) Characterize the newly discovered Sanpodo/Notch signaling pathway. The Notch signaling pathway is an evolutionarily conserved mechanism for modulating cell fate in Drosophila and mammals; in addition, Notch mutations can cause leukemia and other human diseases. Our data indicate that Sanpodo is an actin-binding protein necessary for many Notch-dependent signaling events within the Drosophila CNS. We plan to further characterize the molecular, genetic, and biochemical function of Drosophila and human Sanpodo genes in regulating Notch signaling.

描述(申请人摘要逐字复制)：哺乳动物中枢神经系统 包含许多不同类型的神经元和神经胶质细胞，每种细胞都扮演着特定的角色 在调节运动、感知、认知和整体行为方面的作用。它是 临床上重要的是了解不同的神经细胞类型 ，因为它可以帮助我们识别出 神经退行性疾病、神经系统癌症或行为疾病 精神错乱。确定神经疾病的分子/遗传学基础至关重要 用于开发适当的治疗干预措施。我们用的是果蝇 作为理解神经多样性是如何产生的模型系统。近期 研究表明，果蝇和哺乳动物有着令人惊讶的程度 神经发生调控机制中的保守性。因此，果蝇 研究是发现临床相关基因的有效手段。这个 在此提出的研究的三个具体目标是：(1)确定和 描述建立不同神经细胞类型的基因 中枢神经系统的背腹轴。哺乳动物运动神经元、中间神经元和感觉 神经元沿着中枢神经系统背腹轴的不同区域发育。 在果蝇身上，神经细胞的类型也有差异 背腹轴，但对用于 产生这些截然不同的神经命运。(2)识别和表征基因 建立由单个干细胞产生的不同类型的神经细胞。在……里面 哺乳动物，单个大脑皮层干细胞可以通过 不同的层状命运；在果蝇中，单一的神经干细胞(神经母细胞) 也会产生一种特有的神经元和神经胶质细胞谱系，具有不同的 中枢神经系统内的形态和功能。我们想了解一个人是如何 干细胞可以产生多种类型的神经细胞和神经胶质细胞。(3)特色化 新发现的Sanpodo/Notch信号通路。Notch信令 途径是一种进化上保守的调节细胞命运的机制 果蝇和哺乳动物；此外，Notch突变可导致白血病和 其他人类疾病。我们的数据表明Sanpodo是一种肌动蛋白结合蛋白 许多Notch依赖的信号事件所必需的蛋白质 果蝇属CNS.我们计划进一步确定分子、遗传和 果蝇和人类Sanpodo基因在调节Notch中的生化功能 发信号。