Feedback Induction of a Photoreceptor-specific Isoform of Retinoid-related Orphan Nuclear Receptor beta by the Rod Transcription Factor NRL

Abstract

Vision requires the generation of cone and rod photoreceptors that function in daylight and dim light, respectively. The neural retina leucine zipper factor (NRL) transcription factor critically controls photoreceptor fates as it stimulates rod differentiation and suppresses cone differentiation. However, the controls over NRL induction that balance rod and cone fates remain unclear. We have reported previously that the retinoid-related orphan receptor beta gene (Rorb) is required for Nrl expression and other retinal functions. We show that Rorb differentially expresses two isoforms: ROR beta 2 in photoreceptors and ROR beta 1 in photoreceptors, progenitor cells, and other cell types. Deletion of ROR beta 2 or ROR beta 1 increased the cone: rod ratio similar to 2-fold, whereas deletion of both isoforms in Rorb(-/-) mice produced almost exclusively cone-like cells at the expense of rods, suggesting that both isoforms induce Nrl. Electroporation of either ROR beta isoform into retinal explants from Rorb(-/-) neonates reactivated Nrl and rod genes but, in Nrl(-/-) explants, failed to reactivate rod genes, indicating that NRL is the effector for both ROR beta isoforms in rod differentiation. Unexpectedly, ROR beta 2 expression was lost in Nrl(-/-) mice. Moreover, NRL-activated the ROR beta 2-specific promoter of Rorb, indicating that NRL activates Rorb, its own inducer gene. We suggest that feedback activation between Nrl and Rorb genes reinforces the commitment to rod differentiation.