Gene Regulation Underlying Photoreceptor Neurodegeneration

PROJECT SUMMARY. Retinal degenerative diseases are characterized by the loss of the photoreceptors, the cells within the eye that convert light into signals for vision. Photoreceptors in the mammalian eye are unable to divide or regenerate, and once they are damaged, they cannot be replaced. Thus, patients with retinal degenerative diseases become blind over time and undergo a substantial decrease in their quality of life, as they are no longer able to read, drive or perform independent daily activities. For most of these diseases, treatment to delay photoreceptor cell death and preserve visual response is unavailable. Cellular pathways that promote photoreceptor identity and / or survival have important implications for future clinical therapeutics, such as cellular transplants and reprogramming. Gene activity is controlled by transcriptional regulators, and one group of transcriptional regulators, the PRDM family, has been shown to drive and maintain cell state transitions in a wide range of tissues and cell types. Of interest, one member of the PRDM family, PRDM13, is associated with retinal abnormalities, but no mammalian models existed to examine its activity on the formation of proper retinal cell identities. The overall goal of our research is to determine how PRDM13 regulates retinogenesis and its association with North Carolina Macular Dystrophy. Our central hypothesis is that PRDM13 acts during a critical window of retinal development to cause a shift in cell fate determination disrupting formation of photoreceptors. Completion of the proposed aims will further our understanding of mammalian retinal development by establishing mechanisms for cell fate decisions guided by PRDM13 transcriptional regulation, and how these contribute to healthy retinogenesis.