Determination of Cone Photoreceptor Fate

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Photoreceptors (PRs) are highly specialized cells that transduce light energy into useful physiological signals. In vertebrates, the ciliary PRs, rods and cones, initiate vision. The classical definition of rods and cones is based upon the morphology of the outer segment, a membrane rich organelle specialized for the capture of light and its processing so as to signal other retinal neurons. The range of light intensities over which PRs operate is also a fundamental aspect of their definition, with rods operating in dim light and cones in brighter light. Cones initiate our color and high acuity vision, with cones further defined by the wavelength sensitivity of their opsin. Despite the high value we place on our vision, particularly our conemediated high acuity color vision, we know very little about how cones are generated during development. This information would aid in the efforts to replace them when they fail in many types of diseases leading to blindness. Current stem cell methods are very limited in cone production, principally due to a lack of knowledge regarding the normal developmental cues. New strategies are needed for these methods to produce enough cones to make this an effective therapy. In addition to the benefits for therapeutic applications, knowledge of the mechanisms of PR genesis would inform our understanding of the evolution and development of this important class of sensory neurons. Given the high value of vision, PRs are under heavy selective pressure. This has resulted in a wide variety of PR types, with a blurring of rod and cone definition using classically-defined morphology and physiology. In addition, there are dramatic differences among species in the distribution of rods and the different types of cones across the retina. For example, in humans, there is a small high acuity area, the fovea, where cones are the only PR type. An understanding of how rods and cones are determined would allow for an appreciation of some of the mechanisms that have driven these patterning, morphological, and physiological differences across species. The focus of this grant will be the question of how cones choose their fate during development, utilizing genomic data and modern methodologies. The starting point will be to define the transcription regulation of two key genes required for cone genesis, Otx2 and Oc1, and the downstream events under control of Notch1, the earliest known regulator of cone genesis, and then use these data to derive the cone gene regulatory network(s).