Genetic mechanisms underlying neuronal migration in the developing Drosophila brain

理解人类大脑的1000亿个神经元如何组装形成高度复杂的神经回路，使我们成为我们是谁，是神经生物学的一个基本问题。神经元的连接和组织缺陷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初始的未定型干细胞池发展而来的。为了解决这个问题，我使用果蝇的大脑作为模型系统。尽管体积很小，但苍蝇的大脑包含复杂的神经回路，可以处理各种感官刺激并调节复杂的行为。事实上，果蝇大脑中的某些回路在复杂性上可以与哺乳动物的回路相媲美。在果蝇中开发的复杂的遗传工具，以及其明确的神经解剖学，使其成为一个系统，在这个系统中，脊椎动物中难以回答的问题可以得到解决。* 神经回路形成的关键步骤是神经元从它们出生的地方迁移到它们在成人回路中的最终位置。在这个为期五年的资助过程中，我打算研究果蝇大脑中最大的神经回路--髓质中的神经元迁移。髓质回路的组织和产生其多样性的基因与哺乳动物视网膜中发现的非常相似，使其成为人类眼睛发育的强大模型系统。* 髓质的干细胞产生超过70种类型的神经元，这些神经元可以细分为两组：在成人回路中需要的地方产生的神经元和在较小区域产生的神经元，然后迁移到最终位置。我将使用候选人和无偏见的遗传方法的组合，以及实时成像和表达谱分析技术，以确定控制这些神经元迁移的基因。作为第一步，我发现神经元迁移是由类固醇激素蜕皮激素控制的;当蜕皮激素信号被遗传阻断时，神经元不再迁移并保持聚集在一起。在目标1中，我将确定蜕皮激素信号下游控制神经元迁移的机制和基因。在目标2中，我将研究推动迁移的潜在力量。我将测试两种可能的机制：（1）吸引力可能会引导神经元到正确的位置，（2）神经元之间的排斥力可能会驱使它们彼此远离。在目标3中，我将利用果蝇遗传学的力量，以公正的方式确定迁移所需的基因。由于在哺乳动物的大脑区域（如视网膜和大脑皮层）中也观察到了显著的神经元迁移，因此预计这里发现的一些基因和机制也将在人类发育和疾病中发挥作用。

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.********