Genetic mechanisms underlying neuronal migration in the developing Drosophila brain

了解人类大脑的1000亿个神经元是如何组合形成高度复杂的神经回路的，这些神经回路决定了我们是谁，这是神经生物学的一个基本问题。神经元连通性和组织的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最初的未投入的干细胞池中发展起来的。为了解决这个问题，我用果蝇的大脑作为模型系统。尽管果蝇的体积很小，但它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，苍蝇大脑中的一些电路在复杂性上可以与哺乳动物的电路相媲美。在果蝇身上开发的复杂的遗传工具，以及它明确定义的神经解剖学，使它成为一个系统，在这个系统中，在脊椎动物身上难以回答的问题可以得到解决。***神经回路形成的一个关键步骤是神经元从它们出生的地方迁移到它们在成年回路中的最终位置。在这项为期五年的拨款中，我计划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70多种神经元，这些神经元可以细分为两类：一种是在成人神经回路中恰好需要的地方产生的神经元，另一种是在较小的区域产生的神经元，然后迁移到它们的最终位置。我将结合候选和无偏见的遗传方法，结合实时成像和表达谱技术，来识别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；当蜕皮激素信号被基因阻断时，神经元不再迁移，并保持聚集在一起。在Aim 1中，我将确定作用于Ecdysone信号下游以控制神经元迁移的机制和基因。在目标2中，我将调查驱动迁移的潜在力量。我将测试两种可能的机制：(1)吸引力可能引导神经元到正确的位置；(2)神经元之间的排斥力可能使它们彼此远离。在目标3中，我将使用果蝇遗传学的力量，以一种公正的方式，识别迁徙所需的基因。由于在哺乳动物的大脑区域（如视网膜和大脑皮层）也观察到显著的神经元迁移，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.********