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Activation of the Blue Opsin Gene in Cone Photoreceptor Development by Retinoid-Related Orphan Receptor ß

Department of Human Genetics (M.S.), Mount Sinai School of Medicine, New York, New York 10029; and National Institutes of Health (NIH) (L.N., H.L., L.J., D.F.), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Clinical Endocrinology Branch, Bethesda, Maryland 20892-1772

Address all correspondence and requests for reprints to: Douglas Forrest, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK), Clinical Endocrinology Branch, 10 Center Drive, Bethesda, Maryland 20892-1772. E-mail: forrestd{at}niddk.nih.gov

Color vision requires the expression of opsin photopigments with different wavelength sensitivities in retinal cone photoreceptors. The basic color visual system of mammals is dichromatic, involving differential expression in the cone population of two opsins with sensitivity to short (S, blue) or medium (M, green) wavelengths. However, little is known of the factors that directly activate these opsin genes and thereby contribute to the S or M opsin identity of the cone. We report that the orphan nuclear receptor RORß (retinoid-related orphan receptor ß) activates the S opsin gene (Opn1sw) through binding sites upstream of the gene. RORß lacks a known physiological ligand and activates the Opn1sw promoter modestly alone but strongly in synergy with the retinal cone-rod homeobox factor (CRX), suggesting a cooperative means of enhancing RORß activity. Comparison of wild-type and mutant lacZ reporter transgenes showed that the RORß-binding sites in Opn1sw are required for expression in mouse retina. RORß-deficient mice fail to induce S opsin appropriately during postnatal cone development. Photoreceptors in these mice also lack outer segments, indicating additional functions for RORß in photoreceptor morphological maturation. The results identify Opn1sw as a target gene for RORß and suggest a key role for RORß in regulating opsin expression in the color visual system.

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Nuclear Receptors:   RORβ