Neurons migrate, extend processes, and make a multitude of connections to wire the nervous system during embryonic development. Dynamic rearrangements of the cytoskeleton drive migration of neurons and the elaboration of axons and dendrites. How signaling events link to cytoskeletal elements to influence cell shape change is an intriguing problem that is incompletely understood. Plenty of SH3s (POSH) is a molecular scaffold that interacts with kinases, small G-proteins, and F-actin binding proteins. POSH is expressed in the nervous system during mouse embryogenesis, and RNAi-mediated depletion of POSH reveals a role for POSH in modulating process outgrowth in differentiating mouse neurons. My central hypothesis is that POSH links together kinases, small G-proteins, and cytoskeletal elements to create a functional signaling module that regulates process outgrowth in neurons. We will employ molecular genetic strategies to functionally dissect the role of POSH and its associated proteins in process outgrowth (Aim1). We will test the hypothesis that POSH regulates process outgrowth by promoting the assembly of kinase-substrate complexes (Aim2). To understand how cytoskeletal rearrangements drive process outgrowth, we will probe the organization of the cytoskeleton in neuronal cells, with and without POSH (Aim3). We will test the hypothesis that POSH, in addition to its function in process outgrowth, is required during radial migration of neurons in the developing cortex (Aim4). These studies are expected to provide insight into the mechanisms by which a scaffold protein connects specific signaling events to the cytoskeleton to regulate neuronal process outgrowth. In the long term, understanding the molecular mechanisms that control the formation of axons and dendrites may provide insights into disorders of the human central nervous system, such as mental retardation; it may also contribute to the development of therapeutic approaches for nerve regeneration after injuries to the nervous system.
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