Genetic mechanisms underlying neuronal migration in the developing Drosophila brain

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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.