DESCRIPTION (provided by applicant): This proposal investigates the underlying causes of human ocular diseases using mouse models, focusing on both the Notch signaling pathway, which is broadly required during development, and two classes of bHLH transcription factors (Atoh7/Neurog2 or Hes genes). The activities of both types of factors are regulated by Notch signaling, in particular developmental contexts. The Notch pathway is also responsible for regulating cell proliferation, morphogenesis, differentiation, apoptosis and stem cell maintenance. Dominant mutations in the human Notch pathway genes JAG1 and NOTCH2 cause Alagille syndrome, in which some patients exhibit eye deformities. This proposal will use complex conditional (cre-lox) mouse strains, including double and triple mutants, histology, immunohistochemistry, confocal microscopy, in situ hybridization, mouse embryology, flow cytometry, NEXTgen sequencing, bioinformatics, ChIP, qPCR, and PCR technologies to address basic, mechanistic questions about retinal neuron formation. We will address two important questions, namely 1) Which genes regulate optic nerve head development and maintain the boundary between the retina and optic stalk? 2) What controls retinal progenitor cell differentiation into either a retinal ganglion cell or a cone photoreceptor neuron?

PUBLIC HEALTH RELEVANCE: This research will provide fundamental understanding of the process of optic fissure formation and closure, which ultimately inform the pathogenesis and/or treatment of congenital diseases like coloboma, microphthalmia, optic nerve hypoplasia, Leber's congenital amaurosis, and pediatric and adult onset glaucoma. This research project addresses several objectives recommended by the Retinal Diseases Panel (http://www.nei.nih.gov/strategicplanning/np_retina.asp#obj) which are to "Identify and characterize genes responsible for optic nerve disease" and "Develop transgenic and other animal models of optic nerve disease". In a broader context, our experiments will also contribute new information about Notch signaling regulation of multiple bHLH transcription factors.