The long-term goal of this project is an integrated understanding of the mechanisms of photoreceptor morphogenesis and maintenance with a view to the rational design of therapies of photoreceptor disease and injury. Using Drosophila compound eye photoreceptor as a model system, we propose to continue our studies of the cytoskeleton and membrane fusion in photoreceptor development. These processes are highly conserved among eukaryotes and studies of Drosophila eye development have a proven record for providing useful insights into vertebrate retinal development. Compelling evidence implicates rhodopsin in photoreceptor morphogenesis: vertebrate rod outer segments and invertebrate rhabdomeres fail to develop in mutants lacking rhodopsin. The mechanism of this requirement is not known. Our recent observations lead us to propose that targeted delivery of rhodopsin-rich membrane to the developing photosensitive membrane leads to the localized activation of the small GTPase, Drac1, which, in turn, orchestrates a reorganization of the membrane cytoskeleton essential for rhabdomere morphogenesis.
Specific aims of this proposal will test our model by manipulating candidate genes in the Drac1 pathway as well as identifying additional genes essential for rhabdomere morphogenesis. We further aim to continue characterization of eyes closed (eyc), a Drosophila homolog of p47, the p97 membrane fusion protein co-factor, eyc mutants show defects of development consistent with a failure of accurate membrane delivery, providing an entree into these mechanisms.
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