Human Molecular Genetics Advance Access originally published online on July 25, 2006
Human Molecular Genetics 2006 15(17):2588-2602; doi:10.1093/hmg/ddl185
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In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development
1 Neuroscience Graduate Program, 2 Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center and 3 Department of Human Genetics, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA and 4 Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed: Tel: +1 7347633731; Fax: +1 7346470228; Email: swaroop{at}umich.edu
Received May 31, 2006; Accepted July 19, 2006
Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-cones and supernormal S-cone-mediated vision in humans. To better understand its in vivo function, NR2E3 was expressed ectopically in the Nrl–/– retina, where post-mitotic precursors fated to be rods develop into functional S-cones similar to the human NR2E3 disease. Expression of NR2E3 in the Nrl–/– retina completely suppressed cone differentiation and resulted in morphologically rod-like photoreceptors, which were however not functional. Gene profiling of FACS-purified photoreceptors confirmed the role of NR2E3 as a strong suppressor of cone genes but an activator of only a subset of rod genes (including rhodopsin) in vivo. Ectopic expression of NR2E3 in cone precursors and differentiating S-cones of wild-type retina also generated rod-like cells. The dual regulatory function of NR2E3 was not dependent upon the presence of NRL and/or CRX, but on the timing and level of its expression. Our studies reveal a critical role of NR2E3 in establishing functional specificity of NRL-expressing photoreceptor precursors during retinal neurogenesis.
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