MOLECULAR STUDIES OF RETINAL DEGENERATION IN DROSOPHILA

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The overall objective of this project is to focus on newly generated insertional mutants which display retinal degeneration in Drosophila melanogaster. The strategy for accomplishing this goal involves a recently developed mutagenesis and screening procedure that utilizes P-transposable element containing vectors, called "enhancer trap". The specific aims are to study the cellular and molecular basis for the retinal degeneration using the following approaches. First, obtain lines of flies containing P-transposon insertions, and screen the lines for: 1) LacZ expression in the photoreceptors; 2) disruption of normal visual physiology by ERG analysis; and 3) evidence )f retinal degeneration. Second, the cytogenetic location of the P-transposon insertion will be determined and the effected gene will be cloned and subjected to a detailed molecular characterization. To ensure that the cloned DNA indeed corresponds to the mutated gene, genetic complementation with the cloned DNA will be carried out. We #W then focus on characterizing the gene product defined by the mutation, as well as a biochemical and physiological dissection of the retinal degeneration. Finally, the developmental program for gene expression will )e assessed and the phylogenetic distribution of the gene and its encoded products determined. A combination of these approaches is likely to lead to a characterization of the retinal degeneration, as well as provide important information on how the components of the photoreceptor cells function and are integrated. This project is part of a larger interest in genetically inherited retinal diseases that result in progressive retinal degeneration and eventual blindness. Retinitis pigmentosa (RP) is an example of such a disease in humans. However, due to the difficulty in obtaining human RP ocular tissues, much work has been carried out in animal models. The complexity of human RP degenerations suggest that each one may have a distinct genetic and chemical basis. Therefore, it is expected that results arising from this study will be relevant to at least one of the diseases.