Orphan nuclear receptors and mammalian development

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The development of an organ or tissue often depends upon a genetic hierarchy of control involving the successive activation of a series of genes. The activity of these genes directs the cellular differentiation events that change a largely un-specialized cell mass into a mature and functioning organ. Genes encoding transcription factors are often critical in such developmental pathways. Nuclear receptors are ligand-regulated transcription factors that respond to hormones or other ligands. Orphan receptors are a special sub-class of nuclear receptors that lack known physiological ligands and may have constitutive transcriptional functions. The retinoid-related orphan nuclear receptor b (RORb), encoded by the Rorb gene, is specifically expressed in the brain and retina. The expression pattern in retina is suggestive of functions in neurogenesis and in the subsequent stages of differentiation of photoreceptors. However, the functions of Rorb in retina remain poorly defined. The study of the Rorb gene therefore offers the opportunity to elucidate novel functions for an orphan nuclear receptor in a defined developmental system, the retina. Progress: 1. The role of the Rorb gene in cone development. In dichromatic mammals, cones express opsin photopigments that are sensitive to short (S, blue) or medium-longer (M, green) wavelengths of light. The mechanisms that differentially regulate M and S opsin expression are critical for color vision but are incompletely understood. Our analysis has indicated that the Rorb gene induces the S opsin gene in cone development. The results suggest that the S opsin gene is directly regulated by binding of the RORb protein in cone maturation. 2. Ongoing studies suggest that RORb is also involved in the rod developmental pathway (collaboration with Dr Anand Swaroop, NEI). Preliminary data indicate that these functions are distinct from those in cones. The data suggest that RORb is multi-functional, having independent roles in different retinal cell populations.