Genetic mechanisms underlying neuronal migration in the developing Drosophila brain

果蝇大脑发育中神经元迁移的遗传机制

• 批准号: RGPIN-2015-06457
• 负责人: Erclik, Ted
• 金额: $ 2.55万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708802
• 关键词: Genetic; mechanisms; underlying; neuronal; migration

Summary of Proposal Understanding how the 100 billion neurons of the human brain assemble to form the highly complex neural circuits that make us who we are is a fundamental problem in neurobiology. Defects in the connectivity and organization of neurons have been linked to several neurodevelopmental disorders, including autism. My long-term objective is to understand how complex neural circuits develop from initial pools of uncommitted stem cells. To address this question, I use the brain of the fruit fly as a model system. Despite its small size, the fly's brain contains complex neural circuitry that processes diverse sensory stimuli and mediates sophisticated behaviours. Indeed, some circuits in the fly brain rival mammalian circuits in their complexity. The sophisticated genetic tools that have been developed in the fly, as well as its well-defined neuroanatomy, make it a system in which questions that are difficult to answer in vertebrates can be addressed. A critical step in neural circuit formation is the migration of neurons from where they are born to their final position in the adult circuit. Over the course of this five-year grant, I propose to study neuronal migration in the largest neural circuit of the fly brain, the medulla. The organization of the medulla circuit and the genes that generate its diversity are very similar to those found in the mammalian retina, making it a powerful model system for human eye development. The stem cells of the medulla produce over 70 types of neurons, which can be sub-divided into two groups: neurons that are generated exactly where they need to be in the adult circuit and those that are produced in smaller regions and then migrate to reach their final position. I will use a combination of candidate and unbiased genetic approaches, together with live imaging and expression profiling techniques, to identify the genes that control the migration of these neurons. As a first step, I have found that neuronal migration is controlled by the steroid hormone Ecdysone; when the Ecdysone signal is genetically blocked, neurons no longer migrate and remain clustered together. In Aim 1, I will determine the mechanisms and genes that act downstream of the Ecdysone signal to control neuronal migration. In Aim 2, I will investigate potential forces that drive migration. I will test two possible mechanisms: (1) Attractive forces may guide neurons to the right position and (2) Repulsive forces between neurons may drive them away from each other. In Aim 3, I will use the power of Drosophila genetics to identify, in an unbiased manner, the genes that are required for migration. As significant neuronal migrations are also observed in mammalian brain regions such as the retina and cerebral cortex, it is anticipated that some of the genes and mechanisms uncovered here will also play a role in human development and disease.

提案摘要 了解人脑的1000亿个神经元如何组装出使我们成为我们身份的高度复杂的神经回路，这是神经生物学中的基本问题。神经元连通性和组织的缺陷已与包括自闭症在内的几种神经发育障碍有关。 我的长期目标是了解复杂的神经回路是如何从无所作为的干细胞的初始库中发展出来的。为了解决这个问题，我将果蝇的大脑用作模型系统。尽管尺寸很小，但苍蝇的大脑含有复杂的神经回路，可以处理各种感觉刺激并介导复杂的行为。确实，苍蝇脑中的某些电路竞争哺乳动物电路的复杂性。即时开发的复杂遗传工具及其定义明确的神经解剖学使其成为一个系统，在该系统中，可以在脊椎动物中难以回答的问题。 神经回路形成的关键步骤是神经元迁移到它们在成人电路中的最终位置的迁移。在这项为期五年的赠款过程中，我建议研究蝇大脑最大的神经回路的神经元迁移。延髓电路的组织和产生其多样性的基因与在哺乳动物视网膜中发现的基因非常相似，这使其成为人类眼睛发育的强大模型系统。 髓质的干细胞产生70多种神经元，可以分为两组：精确生成的神经元，这些神经元精确地在成人电路中以及在较小区域产生的神经元，然后迁移以达到最终位置。我将使用候选者和公正的遗传方法以及实时成像和表达分析技术的组合来识别控制这些神经元迁移的基因。第一步，我发现神经元迁移受类固醇激素ecdysone的控制。当ecdysone信号被遗传阻断时，神经元不再迁移并保持聚集在一起。在AIM 1中，我将确定ecdysone信号下游作用以控制神经元迁移的机制和基因。在AIM 2中，我将调查推动迁移的潜在力量。我将测试两种可能的机制：（1）吸引力可以引导神经元到正确的位置，并且（2）神经元之间的排斥力可能会彼此远离。在AIM 3中，我将使用果蝇遗传学的力量以公正的方式识别迁移所需的基因。由于在视网膜和脑皮质等哺乳动物脑区域也观察到明显的神经元迁移，因此预计此处发现的某些基因和机制也将在人类发育和疾病中发挥作用。