Master control genes in the regeneration of rod photoreceptors from endogenous progenitor cells in zebrafish retina

Abstract

Retinitis Pigmentosa is a chronic retinal degenerative disease characterized by the gradual loss of rod, and later, cone photoreceptors until the individual is completely blind. Regeneration of photoreceptors from endogenous progenitor cells is a possible therapeutic approach, but mammals do not do this naturally. Mammalian models can be induced to generate retinal progenitors from Muller glial cells, but there has been limited success in rod photoreceptor specific regeneration. Unlike mammals, zebrafish have the natural ability to regenerate neurons after injury or disease and can provide insight into the molecular mechanisms of regeneration. In this study, we used a zebrafish model of Retinitis Pigmentosa to investigate the class of progenitors responsible for rod photoreceptor regeneration in the context of chronic disease. Using bioinformatic analyses of single-cell RNA sequencing datasets, we identified master regulator genes responsible for proliferation of retinal progenitors, differentiation of progenitors into rod photoreceptors, and maturation of the new rod photoreceptors. Using transient knockdown of gene expression in adult regenerating retina we determined that e2f1, e2f2, e2f3 and aurkb are critical for proliferation of progenitors, and prdm1a is critical for differentiation of progenitors into rod photoreceptors. This study provides a list of master regulators responsible for the specific regeneration of rod photoreceptors during chronic retinal degeneration. Impact StatementIdentification of master regulating genes that drive the proliferation of progenitor cells and their differentiation specifically into rod photoreceptors provides insight that can be used to develop regenerative therapies for retinal degenerative diseases.