SURVIVAL & MATURATION OF NORMAL & MUTANT PHOTORECEPTORS

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Photoreceptor death causes blindness in retinal degenerations such as retinitis pigmentosa and age-related macular degeneration. Although genetic mechanisms trigger several forms of these diseases, cell-cell interactions and microenvironmental factors are also likely to be involved in their pathogenesis. The search for trophic agents supporting the survival and differentiated function of photoreceptor cells is therefore important for the development of strategies for their prevention and/or treatment. Embryonic cell transplantation -- an approach actively explored in many laboratories as a possible treatment for retinal degenerations -- could also benefit from new information on photoreceptor survival- and differentiation-promoting factors. Retinoids of the vitamin A family have been known for many years to be necessary for photoreceptor health and survival, but their mechanisms of action remain poorly understood. New avenues for their investigation have been opened in recent years by the almost explosive growth in information about retinoic acid and its receptors. As part of our long term interest in the study of trophic factors for photoreceptor cells, we have recently observed regulatory effects of retinoic acid and other retinoids upon isolated mouse photoreceptor cells in vitro. These culture systems thus appear as suitable experimental systems for detailed analysis of these issues. The studies proposed here will involve embryonic and neonatal mouse retinas in situ and in explant cultures, as well as purified cultures of retinal neurons and photoreceptors. In situ hybridization, the polymerase chain reaction, and immunocytochemical and autoradiographical methods will be used in a multidisciplinary approach to investigate the expression and distribution of retinoic acid receptors, their developmental regulation, and the responses of retinal neurons and photoreceptors to retinoic acid and other retinoids. It is anticipated that these studies will generate new information regarding the role of retinoids in photoreceptor differentiation and survival, thus contributing to the design of strategies for the prevention and potential treatment of blinding retinal degenerations.