Retinal degenerations are a group of genetically heterogeneous disorders that can often be classified according to the type of pathology observed in rod and cone photoreceptors. These diseases affect one in every 4000 individuals and it is clear the severity of disease is strongly affected by genetic factors. This large group of disorders includes retinitis pigmentosa, macular degeneration, Bardet-Biedl syndrome, Usher syndrome, and enhanced S-cone syndrome (ESCS), each of which has photoreceptor degeneration as a major component of the disease phenotype. Our long-term goal is to understand the transcriptional networks regulating photoreceptor generation and maintenance, which will enable us to identify novel targets that may be amenable for improved treatment strategies for retinal disease. Our studies and those of others demonstrate that the nuclear receptor Nr2e3 functions in multiple transcriptional networks to regulate the development and maintenance of photoreceptor cells. The PI was the first to report that mutations in human Nr2e3 cause the recessive ESCS, and mutations in mouse Nr2e3 cause excess production of blue opsin expressing cone cells with progressive retinal degeneration. Recent findings also demonstrate that mutations in human Nr2e3 can have significant variability in phenotypic manifestation causing a milder ESCS phenotype, Goldman Favre syndrome, or dominant retinitis pigmentosa. This underscores the importance of Nr2e3-directed transcriptional pathways in retinal disease and suggests the existence of human modifier genes influencing these diseases. The objective of this proposal is to identify genetic modifiers of retinal degeneration in the mouse model Nr2e3rd7/rd7. We utilize two approaches: a genetic mapping strategy, and a candidate gene approach to perform our studies.
Aim 1 is to identify the genetic modifier of Nr2e3rd7/rd7, referred to as Mor7, on the AKR/J strain background using a positional cloning approach. We have mapped this modifier gene and developed a congenic line (N9) that ameliorates Nr2e3rd7/rd7 associated retinal degeneration.
Aim 2 is to determine whether the nuclear receptor Nr1d1, a cofactor of Nr2e3, can modify Nr2e3rd7/rd7 associated retinal degeneration. We will test our hypothesis by over-expressing Nr1d1 in newborn Nr2e3rd7/rd7 mice to determine if Nr1d1 can rescue retinal degeneration and retinal explant experiments to determine the effects of altered Nr2e3 or Nr1d1 expression on rod or cone photoreceptor cell fate. Our studies will greatly enhance understanding of genetic factors that influence severity of retinal disease, and, provide potentially powerful targets for improved therapies to treat or prevent multiple forms of retinal disease involving photoreceptor degeneration.

Public Health Relevance

Retinal diseases are debilitating disorders that affect millions of individuals worldwide and can often lead to complete blindness. We propose to use mouse models to identify genes that can correct retinal disease. These genes will be potentially powerful targets that can be used to treat not one but many forms of retinal disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Schepens Eye Research Institute
United States
Zip Code
Olivares, Ana Maria; Han, Yinan; Soto, David et al. (2017) The nuclear hormone receptor gene Nr2c1 (Tr2) is a critical regulator of early retina cell patterning. Dev Biol 429:343-355
Olivares, A M; Jelcick, A S; Reinecke, J et al. (2017) Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina. Sci Rep 7:690
Olivares, Ana Maria; Althoff, Kristen; Chen, Gloria Fanghua et al. (2017) Animal Models of Diabetic Retinopathy. Curr Diab Rep 17:93
Olivares, Ana Maria; Han, Yinan; Soto, David et al. (2017) Corrigendum to ""The Nuclear Hormone Receptor Nr2c1 (Tr2) is a critical regulator of early retina cell pattering"" [Dev. Biol. 16 (2017) 30797-7]. Dev Biol 429:370
von Alpen, Désirée; Tran, Hoai Viet; Guex, Nicolas et al. (2015) Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain. Hum Mutat 36:599-610
Olivares, Ana Maria; Moreno-Ramos, Oscar Andrés; Haider, Neena B (2015) Role of Nuclear Receptors in Central Nervous System Development and Associated Diseases. J Exp Neurosci 9:93-121
Cruz, Nelly M; Yuan, Yang; Leehy, Barrett D et al. (2014) Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease. PLoS One 9:e87942
Mollema, Nissa J; Yuan, Yang; Jelcick, Austin S et al. (2011) Nuclear receptor Rev-erb alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina. PLoS One 6:e17494
Jelcick, Austin S; Yuan, Yang; Leehy, Barrett D et al. (2011) Genetic variations strongly influence phenotypic outcome in the mouse retina. PLoS One 6:e21858
Mollema, Nissa; Haider, Neena B (2010) Focus on molecules: nuclear hormone receptor Nr2e3: impact on retinal development and disease. Exp Eye Res 91:116-7

Showing the most recent 10 out of 11 publications