title: In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development.
abstract: 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.
authors.affiliation: Neuroscience Graduate Program, Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor 48105, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Ritu
authors.initials: R
authors.lastname: Khanna
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009694:Nucleic Acid Precursors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014785:Vision, Ocular
chemical_list: D018398:Homeodomain Proteins; C403073:NR2E3 protein, human; D009694:Nucleic Acid Precursors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C109288:cone rod homeobox protein