The overall objective of this ongoing research program is to understand the molecular basis of cell-cell interactions that regulate retinal neurogenesis during development and regeneration. The accumulated evidence from many laboratories working both in vivo and in vitro and with a number of different vertebrate species suggests that extrinsic signals regulating the differentiation of retinal progenitor cells vary with developmental age and retinal location, and that the competence of retinal progenitors to respond to extrinsic cues is progressively altered during retinal development, reflecting intrinsic changes in retinal progenitors at different ages. However, in teleost fish, retinal neurogenesis continues throughout adult life, and new neurons of all types are generated from multipotent retinal progenitor cells located in the ciliary marginal zone (cmz) at the far peripheral retina, suggesting that the capacity to generate even the 'early born' retinal cells types (e.g., retinal ganglion cells) is retained by retinal progenitors in the cmz of the adult teleost retina. These multipotent progenitors exhibit self-renewal, can generate all retinal cell types, and are mitotically activated in response to injury; therefore, they have all the characteristics of retinal stem cells. In addition, scattered across the differentiated, central retina in adult teleost fish, and associated with Muller glial cells, are occasional, slowly proliferating progenitors, which give rise to clusters of rapidly proliferating, lineage-restricted rod precursors that migrate into the outer nuclear layer and generate new rod photoreceptors. The capacity for ongoing neurogenesis in the fish retina is associated with a robust ability to regenerate: when neurons in the teleost retina are destroyed, under certain conditions they are replaced. The source of regenerated neurons in central retina appears to be the Muller-associated retinal progenitors, which therefore are also retinal stem cells. ? ? The objectives of the proposed research are to: 1) define and characterize the molecular profiles of retinal stem cells and retinal progenitor cells in the embryonic and adult zebrafish (Danio rerio) retina, and establish the molecular/genetic hierarchy, 2) examine the phenotypic plasticity of Muller glial cells in response to retinal injury, and test the hypothesis that they function as retinal stem cells, and 3) identify the intrinsic and extrinsic factors that are necessary and sufficient to define the retinogenic potential of retinal stem cells. ? ? Understanding the molecular mechanisms controlling the proliferation and differentiation of retinal progenitors will have important value for the future development of therapeutic retinal transplantation in patients with retinal degenerative diseases or retinal injuries. Learning more about the characteristics and capabilities of retinal stem cells in the adult fish retina may provide important insights to help reach that goal. ? ?
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