This proposal describes a set of research avenues that will be used to develop an independent research program in regulation of synaptic architecture. The primary scientific goal is to understand how the relationship between signal transduction pathways and actin cytoskeleton regulators controls cellular structures in Drosophila synapses. Neurons must intimately link exocytosis, intracellular vesicle and protein transport, endocytosis, cell adhesion, morphological change and local protein synthesis to achieve appropriate connectivity and synaptic activity. The cytoskeleton links all these processes together but it is not known how. One key signal-responsive actin-binding protein is WASp (Wiskott-Aldrich Syndrome protein), which activates actin filament nucleation by the Arp2/3 complex downstream of Cdc42 and SH3 domain proteins. Nwk (Nervous Wreck) is a conserved neuronal WASp-activating protein that localizes to synaptic periactive zones. In the absence of Nwk, flies suffer from temperature-sensitive seizures, have reduced synaptic bouton size and neurotransmitter release, and exhibit overgrowth of the neuromuscular junction. Therefore, Nwk is an excellent candidate for synaptic regulation of the Arp2/3 complex via WASp. Nwk- WASp interactions are involved in endosomal traffic of synaptic growth factor signaling complexes but the function of actin polymerization in this process is not understood. The scientific goals of this proposal are (1) to determine how a conserved Nwk-interacting protein contributes to its function in endosomal traffic; and (2) to obtain high resolution images of endocytic and endosomal structures in periactive zones, a specialized subdomain of the synapse involved in both recycling of synaptic vesicles and in cell adhesion and synaptic growth, to gain insight into their function. The training goals of this proposal are to develop electron tomography techniques for high resolution imaging of subcellular domains involved in synaptic growth. Misregulation of synaptic growth is a hallmark of many neurological diseases, including epilepsy, Alzheimer's disease and mental retardation. Mutations in WRP, a human homolog of NWK, have been linked to inherited childhood mental retardation. Therefore, elucidation of the conserved subcellular trafficking pathways and structures regulated by NWK will help interpret human diseases and provide new targets for therapies.
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