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 an immature, non-specialized cell mass into a mature, functioning organ. 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 but are capable of directing critical transcriptional functions in development and homeostasis. The retinoid-related orphan nuclear receptor b, encoded by the Rorb gene, is specifically expressed in the brain and retina. However, the neurodevelopmental functions of Rorb remain incompletely understood. The study of the Rorb gene therefore offers the opportunity to elucidate novel functions for an orphan nuclear receptor in a defined neurodevelopmental system. Progress: 1. The role of Rorb in neurodevelopment. We have investigated in detail the expression pattern of the Rorb gene in retina. The pattern is suggestive of functions in the differentiation of photoreceptors and other cell types. We continue our investigation of the specific role of the Rorb gene in directing the differentiation of both cone and rod photoreceptors. In dichromatic mammals, cones express opsin photopigments that are sensitive to short (S, blue) or medium-longer (M, green) wavelengths of light whereas rods mediate detection of dim light. Our investigations have also established that Rorb is critical for the generation of two classes of retinal interneurons: horizontal cells that modify synaptic transmission between photoreceptors and bipolar neurons, and amacrine cells that modify transmission between bipolar neurons and ganglion cells. 2. The Rorb gene is remarkable for the variety of different functions it controls in retinal development. To investigate how a single gene can control distinct neurodevelopmental functions, we continue to investigate the roles of two N-terminal splice variant products encoded by the Rorb gene. Our studies are investigating how these variant N-terminal products provide additional versatility in directing cell-specific functions in retinal development. Targeted deletions of these Rorb1 and Rorb2 isoforms have been generated in mammalian models and the functional consequences are being determined to indicate how this developmental control gene is capable of regulating several different cell-specific functions.

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