This proposal is about the control of cell determination in the nervous system: what regulates the kinds and numbers of neurons and glial cells produced? The emerging consensus is that lineage is not the essential determinant of retinal cell proliferation or differentiation. An alternative hypothesis is that cell-cell interactions provide important permissive or instructive signals. The model system used n the proposed studies is the teleost retina, chosen because it has a limited number of well-defined, highly-ordered neuronal types, including rods and several morphologically and spectrophotometrically distinct cone types, and it has a prolonged developmental period and the capacity to regenerate. The proposed experiments focus on cell interactions and positional cues that might be important in controlling cell proliferation and photoreceptor differentiation, especially the role of non-neuronal cells (Muller glia and retinal pigmented epithelium) and hierarchical decision strategies that might influence the choice to become a rod or a cone. Cell-specific monoclonal antibodies and cell-specific molecules (enzymes, carbohydrate moieties, etc.) are to be used as markers of commitment and differentiation, and retinal cell proliferation, differentiation and regeneration will be studied both in vivo, in larvae and adult animals, and in cultures of dissociated retinal cells that are allowed to reaggregate in vitro. These studies will provide information about photoreceptor genesis, and may reveal important differences between rods and cones that might lead to a better understanding of disease processes that differentially affect rods (such as retinal degenerations and light- damage) and other ocular pathologies that involve abnormal proliferation of retinal glia and/or retinal pigmented epithelial cells (such as diabetic retinopathy and proliferative vitreoretinopathy).
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