MECHANISMS OF ADAPTATION IN MAMMALIAN CONES

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DESCRIPTION (provided by applicant): Cones represent only 5% of photoreceptors in humans, but are critical for our daytime vision. AMD, the most prominent cone vision disorder, has a major impact on the elderly, and cone loss results in legal blindness. It is critical for the function of mammalian cones as daytime photoreceptors that they regenerate their visual pigment rapidly following its destruction by light. This is made possible by two pathways. The canonical retinal pigment epithelium (RPE) visual cycle provides 11-cis retinal chromophore to both rods and cones. In contrast, the novel retina visual cycle relies on Muller cells to provide 11- cis retinol, which can be utilized only by cones after they oxidize it to 11-cis retinal by an unknown dehydrogenase. As we demonstrated over the past five years, the retina visual cycle plays a crucial role in daytime vision by extending the functional range of cones to bright light and by driving their rapid dark adaptation. The scarcity of cones in the mammalian retina makes molecular and biochemical cone-specific studies extremely challenging. As a result, the molecular mechanism that enables cones, but not rods, to use the retina visual cycle is not understood. The mutant rd7 mouse, which lacks the rod transcription factor Nr2e3 and has rods that in addition to its rod genes express a subset of cone genes, provides us with a unique opportunity to identify the molecular mechanism controlling access to the retina visual cycle. The central hypothesis of this proposal is that the molecular properties of photoreceptors control their ability to use the retina visual cycle. Specifically, we will demonstrate that the expressionof a subset of cone genes in the rd7 rods is sufficient to enable them to use 11-cis retinol for pigment regeneration and to access the retina visual cycle. Expression analysis of rd7 rods has allowed us to identify retinol dehydrogenase 10 (RDH10) as a cone-specific gene and the likely key enzyme that oxidizes 11-cis retinol as part of the retina visual cycle. We will use loss and gain of function mutant mice to demonstrate the role of RDH10 in the retina visual cycle. Collectively, the experiments outlined here will identify the molecular mechanism that enables cones to access the retina visual cycle and regenerate rapidly their visual pigment, a property that is critical for daytime, cone-mediated vision in bright and rapidly changing light conditions. They will also provide new therapeutic tools for the treatment of visual disorders caused by faulty RPE visual cycle.