Human Molecular Genetics Advance Access published online on July 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl185
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1 Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI; Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI
* To whom correspondence should be addressed. 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.
Received May 31, 2006
Revised July 19, 2006
Accepted July 19, 2006
Article
In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development
Hong Cheng 1, Tomas S. Aleman 2, Artur V. Cideciyan 2, Ritu Khanna 3, Samuel G. Jacobson 2, and Anand Swaroop 4 *
2 Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA
3 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI
4 Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI; Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI; Department of Human Genetics, University of Michigan, Ann Arbor, MI; W. K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA
Anand Swaroop, E-mail: swaroop{at}umich.edu
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