Genetic analysis of cone photoreceptor determination

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DESCRIPTION (provided by applicant): Retinal photoreceptors are highly specialized neurons with unique, differentiated features associated with detection of photons and transduction of neural signals. The distribution, spacing and spectral identity of individual photoreceptor subtypes is an important parameter that influences many properties of visual function, including sensitivity to low levels of light, visual acuity, color vision, etc. Most vertebrates, including zebrafish, have multiple spectral classes of cone photoreceptors as well as rod photoreceptors. However, the molecular control of photoreceptor determination and cell fate choice, especially the mechanisms that regulate choice of cone spectral classes, are poorly understood. In part, this is because the typical model system (rodents) have rod-dominated retinas. In contrast, teleost fish have abundant cone photoreceptors, and the zebrafish has emerged as a powerful model for forward genetic studies to discover developmental regulatory genes. The objective of the proposed mutagenesis screen is to characterize zebrafish mutants that selectively disrupt cell fate determination of cone photoreceptors in the developing retina and to identify the genes involved. The cone photoreceptors in zebrafish retina include four spectral types, each of which expresses a specific opsin gene that produces a visual pigment with a maximum absorption at wavelengths corresponding to red, green, blue or ultraviolet, respectively. The cones in the zebrafish retina form a precise mosaic pattern such that rows of red and green double cones alternate with rows of blue and ultraviolet single cones, superimposed on an intrinsic pattern of reiterative, mirror-image symmetry. The cone mosaic pattern is generated in a curvilinear wave of differentiation that sweeps across the presumptive photoreceptor layer from optic stalk to retinal margin. The mechanisms that control cell fate determination of cone photoreceptors to produce this highly ordered spatial array are not known. The precision of the spatial and temporal organization of the cone mosaic pattern makes this an ideal model system in which to identify genes that perturb the organization and cell type specification of cone photoreceptors. The rationale for studying cone photoreceptor cell fate determination and patterning is that alterations in the fundamental developmental processes that lead to neuronal specification are thought to be responsible for a number of congenital malformations of the human brain and retina, which impair neuronal function and can result in mortality, morbidity, physical or mental disabilities. Discovering the molecular mechanisms that pattern the cone photoreceptor array in the zebrafish retina will lead to a better understanding of the factors that regulate choice of retinal cell fate and mediate visual behaviors.