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The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene  Rev-erb alpha/Nr1d1  has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of  Rev-erb alpha/Nr1d1  in the retina, we evaluated the effects of loss of  Nr1d1  to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene  Nr2e3  in the developing and mature retina. Knock-down of  Nr1d1  expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include:  Nr2c1, Recoverin ,  Rgr ,  Rarres2 ,  Pde8a , and  Nupr1 . We examined the cyclic expression of  Nr1d1  and  Nr2e3  over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for  Nr1d1 , in conjunction with its cofactor  Nr2e3 , in regulating transcriptional networks critical for photoreceptor development and function.

Nuclear Receptor Rev-erb Alpha (Nr1d1) Functions in Concert with Nr2e3 to Regulate Transcriptional Networks in the Retina