Transcriptional regulation of photoreceptor identity and function

About This Grant

PROJECT SUMMARY/ABSTRACT Vision loss caused by the death of photoreceptors is a leading cause of irreversible blindness worldwide, yet therapeutic options remain limited. For this reason, the NEI’s Retinal Disease Program has identified the development of strategies for the treatment of retinal degenerations as a core program goal. Recently, several laboratories have derived photoreceptors from stem cells, making cell-replacement therapies particularly promising. Additionally, important advances have been made into manipulations that could stimulate retinal regeneration from the retinal Müller glia. The critical barrier for the success of such therapies is to understand the factors required to direct fate decisions in progenitors towards fully differentiated cell subtypes that are also capable of properly rewiring into retinal circuits. Although key transcription factors have been identified as essential for generating retinal cell classes, the target genes required to generate each retinal cell subtype are still undetermined. TBX2 is a central transcriptional regulator of all photoreceptor subtypes and is highly conserved across vertebrates. Our main hypothesis for this proposal is that retinal progenitors express TBX2 to repress the identity of photoreceptor subtypes that are not UV cones through two different mechanisms, and our main goal is to identify these two roles. Three Specific Aims are proposed: Specific Aim 1 will test the hypothesis that tbx2a and tbx2b have subdivided functions and their roles in generating photoreceptor subtypes are different. Specific Aim 2 will identify candidate factors downstream of TBX2 important for the generation of photoreceptor subtypes. Specific aim 3 will test the hypothesis that differences in Tbx2a and Tbx2b function are caused by differences in the repression domain. At the successful completion of this project, I will have identified the subdivided functions of tbx2a and tbx2b and subsequent targets to generate and maintain photoreceptor subtypes. This proposal benefits from the experimental accessibility of the retina and our deep knowledge of retinal cell types and circuits, but our approach has the potential to impact the study of other neuronal degenerative diseases. In addition to my proposed research, I designed a holistic training plan that will help me advance toward my goal of leading an independent research lab. The work planned for the F31 award period will be valuable in terms of both research and training opportunities.