Proper regulation of synaptic growth is fundamental to the formation and plasticity of neural circuits. Defects in synaptic development and plasticity are associated with a broad range of neurological disorders including mental retardation, motor, cognitive and psychological impairments, and neurodegeneration. However, the molecular mechanisms regulating these processes remain incompletely understood. Using the Drosophila larval NMJ as an experimental model to investigate these processes, I have carried out the detailed characterization of Nervous wreck (Nwk), a key negative regulator of synaptic growth, while, in parallel, expanding my investigations through the identification of additional genes required for the proper growth of synapses, nwk encodes a neuron-specific SH3-domain protein that functions with Wasp. Significantly, a human Nwk-family member has been implicated in a severe form of mental retardation. I have identified a role for Nwk in the endocytic regulation of BMP growth signaling at synapses. Specifically, I found that Nwk interacts functionally and physically with components of the endocytic machinery, including dynamin and Dap160/lntersectin and negatively regulates retrograde BMP growth signaling through a physical interaction with the BMP receptor Thickveins. Synaptic overgrowth in nwk is sensitive to levels of BMP signaling and loss of nwk facilitates BMP-induced synaptic overgrowth. Conversely, overexpression of Nwk suppresses BMP-induced synaptic overgrowth. Moreover, levels of downstream effector phosphorylated MAD are substantially increased in nwk mutants and decreased in motor neurons overexpressing Nwk, directly demonstrating the ability of Nwk to downregulate BMP signaling. The goal of this proposal is to uncover the molecular mechanism by which Nwk regulates BMP signaling at synapses (Aim 1), and to obtain a more complete understanding of synaptic growth control by characterizing a novel synaptic growth regulator identified in my genetic screens (Aim 2). Because of the central importance of synaptic growth regulation to normal neural function and behavior and because the molecular mechanisms that mediate synaptic development and plasticity are very likely to be conserved, elucidating the role of nwk and other novel genes in synaptic growth regulation in Drosophila should provide important insights into mechanisms that may be impaired in human neurological disorders and identify potential targets for therapeutic intervention.
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