SUMMARY: The proper execution of transcriptional programs in retinal progenitor cells is extremely critical for retinal formation as dysregulation of this process leads to severely compromised retinogenesis and the development of ocular disorders, including anophthalmia or microphthalmia. The wiring and rewiring of chromatin landscape constitutes an essential mechanism to precise spatial and temporal regulation of gene expression during retinal differentiation, yet our understanding to this process remains inadequate. Our goal is to utilize state-of-the-art genomic technologies to provide a deep understanding to the genetic and epigenetic circuits that underlie retinal transcription programs and how perturbations in the retinal core regulatory networks lead to congenital syndromes. In the first aim of this proposal, we will use mouse models to dissect the molecular, cellular, and genomic effects of genetic mutations on retinal development. In aim 2, we will elucidate how the chromatin landscape is wired by transcription factors in retinal progenitor cells. In aim 3, we will explore how coordination among components of the core regulatory network drive retinogenesis epigenetically and transcriptionally. When completed, the results of this proposal will bridge a gap in our understanding to the chromatin-based regulatory mechanism underlying retinal genesis, a necessary knowledge to enhance strategies to diagnose, treat or prevent the devastating consequences of congenital vision deficiency.

PROJECT NARRATIVE Genetic mutations in the transcription factor networks that govern eye development are a leading cause of congenital ocular malformations. The proposed studies in this project seek to elucidate novel insights into the mechanisms through which key regulatory circuits active in retinal progenitor cells contribute to the proper production of retinal neurons. This information is critical for a better understanding of the etiology of retinal developmental disorders and for potentially improving diagnosis and management.