This proposal investigates the underlying causes of human ocular diseases using mousemodels. We focus on the Notch signaling pathway, which is critically required in multiplemammalian tissues. In particular, Notch signaling regulates proliferation, apoptosis, cellshape changes, differentiation and stem cell maintenance. Experiments in this proposalwill 1) elucidate the epistatic relationship between Notch signaling and Math5 duringretinal ganglion cell (RGC) neurogenesis 2) explore the multiple retinal neuronphenotypes of Rbpj, and 3) define the requirements of the Notch ligand Deltalike1 duringretinal neurogenesis. Because Notch signaling is widely employed during development,mouse mutations in most Notch pathway genes have already been created. Usingtargeted deletion mice (wholly mutant and conditional alleles), we propose to understandthe requirements for canonical Notch signaling during retinal ganglion cell and cone androd photoreceptor formation. Some studies will employ conditional (cre-lox) mousestrains, histology, immunohistochemistry, in situ hybridization, mouse embryology andPCR genotyping. Others will test regulatory relationships in vitro using a humanretinoblast cell line and biochemical assays. These studies will contribute fundamentalinformation retinal progenitor cell growth, morphogenesis and differentiation, which occurthroughout all metazoan development. This work will yield a better understanding ofcone-rod dystrophies, optic nerve aplasia, hypoplasia, as well as contribute to basicmechanisms of retinal cell development with direct relevance to gene- or cell-basedretinal therapies. Findings here will also be widely useful to the pathologies of CADASILand Alagille Syndromes, and cancer biology, since abnormal expression of Notchpathway genes occurs in each of these diseases.
The goal of this study is to understand the underlying molecular mechanisms of how mammalian retinal neurons forms, using mouse models. We propose to do this by investigating which aspects of retinal formation require the Notch cell-to-cell signaling pathway, and how it regulates the Math5 bHLH transcription factor. In other parts of the body, Notch signaling controls cell shape changes, growth, and death. For these reasons, mutations in the Notch pathway can cause cancer. A thorough understanding of how, when and where Notch acts in the retina has only been addressed superficially. These studies will provide deeper understanding, at the single cell level, of how the retina develops and contribute to the better design of disease therapies for diseases such as Leber's congeital amaurosis, cone-rod distrophy, color blindness, optic nerve aplasia/hyplasia and glaucoma.
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