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

Abstract

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.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

“…2 In fact, NR2E3 has been shown to interact with another orphan NR, NR1D1 (Rev-Erbα), in mice, and functions within the same transcriptional system. 29,31,47 In support of this, shRNA-mediated knockdown of Nr1d1 in the mouse retina reportedly results in a retinal phenotype similar to that observed in the rd7 mice. 31 Furthermore, the therapeutic strategy of gene delivery of Nr1d1 to the retina, performed in neonatal Nr2e3 rd7/rd7 mice, was able to rescue retinal spotting and dysplasia associated with Nr2e3 loss.…”

“…29,31,47 In support of this, shRNA-mediated knockdown of Nr1d1 in the mouse retina reportedly results in a retinal phenotype similar to that observed in the rd7 mice. 31 Furthermore, the therapeutic strategy of gene delivery of Nr1d1 to the retina, performed in neonatal Nr2e3 rd7/rd7 mice, was able to rescue retinal spotting and dysplasia associated with Nr2e3 loss. Finally, Nr1d1 gene delivery was also able to reregulate the key genes that are vital for photoreceptor homeostasis, which were misregulated by the absence of Nr2e3 in Nr2e3 rd7/rd7 mice.…”

Cone Vision Changes in the Enhanced S-Cone Syndrome Caused byNR2E3Gene Mutations

“…[16][17][18][19][20] and experiments now suggest that nuclear receptors can be modulators of disease and could play a role in therapy, including the retinal degeneration resulting from NR2E3 mutations. 21,22 Given the possibility of therapy, the present study was performed using both cross-sectional and longitudinal studies of patients with NR2E3 mutations to begin to understand how this unique group of diseases could be monitored through a clinical trial intending to alter therapeutically the natural history of disease.…”

Potential of Small Molecule–Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa

“…In addition to Nr2e3, Nr1d1 (RevErbα), and Nr3b2 (ERRβ) are important in rod photoreceptor development and maintenance. 40,41 Retinoic acid receptor–related orphan receptor beta (RORβ) coordinates the development of rods and cones, by activating expression of Nrl . 42 Although our evidence suggests that Nr2e3 is a potential target of PR1, it is also possible that one of these other nuclear receptors binds PR1 as well.…”