Investigation of Mammalian Retinal Neuron Development

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Abstract This proposal investigates the underlying causes of human ocular diseases using mouse models. We focus on the Notch signaling pathway, which is critically required in multiple mammalian tissues. In particular, Notch signaling regulates proliferation, apoptosis, cell shape changes, differentiation and stem cell maintenance. Experiments in this proposal will 1) elucidate the epistatic relationship between Notch signaling and Math5 during retinal ganglion cell (RGC) neurogenesis 2) explore the multiple retinal neuron phenotypes of Rbpj, and 3) define the requirements of the Notch ligand Deltalike1 during retinal neurogenesis. Because Notch signaling is widely employed during development, mouse mutations in most Notch pathway genes have already been created. Using targeted deletion mice (wholly mutant and conditional alleles), we propose to understand the requirements for canonical Notch signaling during retinal ganglion cell and cone and rod photoreceptor formation. Some studies will employ conditional (cre-lox) mouse strains, histology, immunohistochemistry, in situ hybridization, mouse embryology and PCR genotyping. Others will test regulatory relationships in vitro using a human retinoblast cell line and biochemical assays. These studies will contribute fundamental information retinal progenitor cell growth, morphogenesis and differentiation, which occur throughout all metazoan development. This work will yield a better understanding of cone-rod dystrophies, optic nerve aplasia, hypoplasia, as well as contribute to basic mechanisms of retinal cell development with direct relevance to gene- or cell-based retinal therapies. Findings here will also be widely useful to the pathologies of CADASIL and Alagille Syndromes, and cancer biology, since abnormal expression of Notch pathway genes occurs in each of these diseases.