Retinoic acid receptor-related orphan receptor alpha regulates a subset of cone genes during mouse retinal development

Color vision is supported by retinal cone photoreceptors that, in most mammals, express two photopigments sensitive to short (S-opsin) or middle (M-opsin) wavelengths. Expression of the Opn1sw and Opn1mw genes, encoding S-opsin and M-opsin, respectively, is under the control of nuclear receptors, including thyroid hormone receptor beta 2 (TR beta 2), retinoid X receptor gamma (RXR gamma), and ROR beta, a member of the retinoic acid receptor-related orphan receptor (ROR) family. We now demonstrate that ROR alpha, another member of the ROR family, regulates Opn1sw, Opn1mw, as well as Arr3 (cone arrestin) in the mouse retina. ROR alpha expression is detected in cones by postnatal day 3 and maintained through adulthood. The retinas of staggerer mice, carrying a null mutation of ROR alpha, show significant down-regulation of Opn1sw, Opn1mw, and Arr3. ROR alpha acts in synergy with cone-rod homeobox transcription factor (Crx), to activate the Opn1sw promoter in vitro. Chromatin immunoprecipitation assays reveal that ROR alpha directly binds to the Opn1sw promoter, Opn1mw locus control region, and the Arr3 promoter in vivo. Our data suggest that ROR alpha plays a crucial role in cone development by directly regulating multiple cone genes.