Retinal degeneration is one of the most common causes of retinal dysfunction, including blindness. Preventing and ultimately curing such diseases depends on understanding the cellular and molecular mechanisms responsible for differentiation and maintenance of retinal cells. Understanding of retinal development requires learning how the final phenotype of retinal cell results from sequential changes in its gene expression combined with instructive signals from its microenvironment. We propose experiments to address specific questions about retinal development using a model organism that allows access to retinal progenitor cells as they progress towards their final fate. We will trace the lineage of individual progenitor cells to measure how cell fate choices change with time. We will then challenge the progenitor by transplanting then to new environments to test the role of extrinsic and intrinsic factors in cell fate choice. We have shown that insulin-like growth factor-I (IGF-I), secreted by cone photoreceptors, regulates rod photoreceptor progenitor fate. By comparing gene expression between dividing and differentiating rod progenitors, we have determined that estrogen receptor alpha (ERalpha) may be specific to dividing cells. In other systems, ERalpha activates the IG-I pathway; thus we propose experiments to discover whether he mitogenic hormones estrogen might play a role in regulating retinal cell division via the IGF-I pathway. Given our success comparing genes expressed in different progenitor populations, we will use this method to characterize differences in gene expression between rod progenitors and other retinal progenitor cells. We also propose experiments designed to elucidate the function of transcription factors known to be important in retinal development from previous experiments in our model system and other species. Since we have previously shown that two secreted factors, IGF-I and basic fibroblast growth factor (FGF-2), are important in regulating progenitor division and differentiation, we now propose experiments to expand our knowledge of the role these factors and their receptors, as well as additional factors (CNTF, TGFalpha, and EGF),. Play in retinal cell fate. Although it is now clear than many organisms, including mammals, add new neurons to functional nervous systems as adults, it is not yet known how such new cell addition is regulated. Since in our retinal model new rod photoreceptors are integrated into fully functional retinal tissue, this may serve as a particularly useful model for understanding adult neurogenesis.
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