Vision is an important sensory modality in animals, and defects in human vision typically result in retinal degeneration. The fruit fly, Drosophila melanogaster, is an excellent animal model to dissect phototransduction and human diseases affecting vision. Fly vision and many other processes rely on phosphoinositide-specific phospholipase C (PLC). In the first part of my thesis, I identified a PLC regulator, STOPS, which is required for the cessation of the light stimulus in Drosophila. Mutation of stops resulted in a reduced concentration of a photoreceptor-specific PLCbeta, encoded by norpA. NORPA has been proposed to have dual roles as a PLC and GTPase activating protein (GAP). We found that the defect in termination in the stops1 mutant resulted from the reduced GAP activity associated with the low levels of NORPA, but not the reduced PLC activity. STOPS is the first protein identified that specifically regulates PLCbeta protein concentration. In the second part of my thesis, I established flies as a model for human retinal diseases caused by defects in visual cycle. The visual cycle is an enzymatic pathway employed in the vertebrate retina to regenerate the chromophore following its release from light-activated rhodopsin. However, a visual cycle is thought to be absent in invertebrates such as Drosophila. Here, we demonstrate that an enzymatic visual cycle exists in flies for chromophore regeneration, and requires a retinol dehydrogenase, PDH, in retinal pigment cells. Absence of PDH resulted in progressive light-dependent loss of rhodopsin and retinal degeneration. These defects were suppressed by introduction of a mammalian dehydrogenase, RDH12, which is required in humans to prevent retinal degeneration. Our results establish flies as an animal model for studying the visual cycle and retinal diseases associated with chromophore regeneration.
展开▼
