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Human Molecular Genetics Advance Access originally published online on February 2, 2005
Human Molecular Genetics 2005 14(6):747-764; doi:10.1093/hmg/ddi070
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved

The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes

Guang-Hua Peng1, Omar Ahmad3, Faisel Ahmad4, Jianfeng Liu1 and Shiming Chen1,2,*

1Department of Ophthalmology and Visual Sciences, 2Department of Molecular Biology and Pharmacology, 3The M.D. program, Washington University School of Medicine, St Louis, MO 63110, USA and 4The M.D. Program, Southern Illinois University School of Medicine, Springfield, IL 62794, USA

* To whom correspondence should be addressed at: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8096, St Louis, MO 63110, USA. Tel: +1 3147474350; Fax: +1 3147474211; Email: chen{at}vision.wustl.edu

Received November 9, 2004; Accepted January 24, 2005

Nr2e3 is an orphan nuclear receptor expressed specifically by retinal photoreceptor cells. Mutations in Nr2e3 result in syndromes characterized by excess blue cones and loss of rods: enhanced S-cone syndrome (ESCS) in humans and rd7 in mice. Using yeast two-hybrid screens with Nr2e3 as bait, the cone–rod homeobox protein Crx was identified as an interacting partner of Nr2e3. Immunoprecipitation assays confirmed this Nr2e3–Crx interaction and identified the DNA-binding domain of each protein as the interaction motif. Immunohistochemistry demonstrated that Crx and Nr2e3 are co-expressed by rod photoreceptors and their precursors. Chromatin immunoprecipitation assays on mouse retina demonstrated that Nr2e3 and Crx co-occupy the promoter/enhancer region of several rod and cone genes in the rod photoreceptor cells. The promoter/enhancer occupancy of Nr2e3 is Crx-dependent, suggesting that Nr2e3 is associated with photoreceptor gene targets by interacting with Crx. Transient transfection assays in HEK293 cells demonstrated that Nr2e3 enhances rhodopsin, but represses S- or M-cone opsin transcription when interacting with Crx. Quantitative real-time RT–PCR analysis on postnatal day 28 (P28) retina of the rd7 mouse, which lacks Nr2e3 protein, revealed an up-regulation of cone genes, but down-regulation of rod genes. Several mutant forms of human Nr2e3 identified from ESCS patients showed defects in interacting with Crx and/or in transcriptional regulatory function. Altogether, our findings suggest that Nr2e3 is a dual-function transcriptional regulator that acts in concert with Crx to promote and maintain the function of rod photoreceptors.


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