The goal of the proposed studies is to investigate the cellular and molecular mechanisms by which the activin subfamily of the TGFbeta family of factors may regulate retinal development and degeneration. Activins are biologically diverse, dimeric signaling peptides that affect cell survival and differentiation in many systems. The activin subfamily is expressed ina distinct spatial pattern during early mouse eye development, but temporal information is absent. This suggests an as yet undefined role for activins during retinal neurogenesis. The finding that photoreceptor cell death in hereditary retinal degenerations occur via apoptosis, an otherwise, natural process in retinal development, together with the knowledge that rod-specific mutations produce both and cone death in human retinitis pigmentosa (RP) and in mouse models of RP, emphasizes the importance of trophic factors in retinal cell survival and further suggests a connection with developmental processes. To investigate the potential role of the activin subfamily in retinal development and disease, the proposed studies will first examine the presence of the activin subfamily in mouse retina during development and prior to, during and following degenerative processes using the reverse transcription polymerase chain reaction, in situ hybridization, immunocytochemistry and RNAse protection assay. Second, the biological effects of the activin subfamily on retinal cells will be investigated using the tool of cell culture. Third, expression of follistatin and the activin receptor IIB are sensitive to retinoic acid (RA), a powerful regulator of development, therefore RA treatment of cultured retinal cells and subsequent responses to activins will be explored. In conclusion, the proposed studies will employ a multi-disciplinary approach to increase substantially our knowledge of mechanisms of retinal development and contribute to the formulation of clinical strategies for the treatment of retinal degenerations.
