Photoreceptor Development and Regeneration in the Vertebrate Retina

Retinitis pigmentosa (RP) is a heritable retinal degenerative disease for which there is currently no cure. To develop cell transplantation therapies, protocols for the in vitro culture and differentiation of retinal progenitor cells must be established that will promote their terminal differentiation, integration, and survival once transplanted. DefIning the regulatory networks that trigger these events in vivo is a necessary next step for the evolution oftransplantation strategies. A long-term goal ofour laboratory is to defIne at a molecular level the steps ofphotoreceptor development and regeneration. We use the powerful zebrafIsh model, which posseses the capacity to regenerate retinal neurons in response to experimental damage. Understanding how the zebrafIsh accomplishes photoreceptor regeneration in vivo will inform efforts to implement a similar genetic program in vitro for therapeutic purposes. Here we outline a proposal to defIne the role of two transcriptioI). factors, Sox IIband Insmla, during retinal development and photoreceptor regeneration. Furthermore, we propose the development ofa novel inducible system that allows careful time course analysis of photoreceptor degeneration and renewal. This work will bridge important gaps in our understanding ofthe molecular mechanisms ofvertebrate photoreceptor development and regeneration, and reveal underlying principles relevant to the development of approaches for the effective treatment of human retinal disease.