title: Feedback induction of a photoreceptor-specific isoform of retinoid-related orphan nuclear receptor β by the rod transcription factor NRL.
abstract: Vision requires the generation of cone and rod photoreceptors that function in daylight and dim light, respectively. The neural retina leucine zipper factor (NRL) transcription factor critically controls photoreceptor fates as it stimulates rod differentiation and suppresses cone differentiation. However, the controls over NRL induction that balance rod and cone fates remain unclear. We have reported previously that the retinoid-related orphan receptor β gene (Rorb) is required for Nrl expression and other retinal functions. We show that Rorb differentially expresses two isoforms: RORβ2 in photoreceptors and RORβ1 in photoreceptors, progenitor cells, and other cell types. Deletion of RORβ2 or RORβ1 increased the cone:rod ratio ∼2-fold, whereas deletion of both isoforms in Rorb(-/-) mice produced almost exclusively cone-like cells at the expense of rods, suggesting that both isoforms induce Nrl. Electroporation of either RORβ isoform into retinal explants from Rorb(-/-) neonates reactivated Nrl and rod genes but, in Nrl(-/-) explants, failed to reactivate rod genes, indicating that NRL is the effector for both RORβ isoforms in rod differentiation. Unexpectedly, RORβ2 expression was lost in Nrl(-/-) mice. Moreover, NRL activated the RORβ2-specific promoter of Rorb, indicating that NRL activates Rorb, its own inducer gene. We suggest that feedback activation between Nrl and Rorb genes reinforces the commitment to rod differentiation.
authors.affiliation: From the Laboratory of Endocrinology and Receptor Biology, NIDDK, and.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Laboratory of Endocrinology and Receptor Biology, NIDDK, and.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Laboratory of Endocrinology and Receptor Biology, NIDDK, and.
authors.forename: Lily
authors.initials: L
authors.lastname: Ng
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jung-Woong
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Hong
authors.initials: H
authors.lastname: Hao
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: From the Laboratory of Endocrinology and Receptor Biology, NIDDK, and forrestd@niddk.nih.gov.
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2 / Q000235:genetics / Q000378:metabolism*; D055355:Opsins / Q000235:genetics / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; C084884:Nrl protein, mouse; D057095:Nuclear Receptor Subfamily 1, Group F, Member 2; D055355:Opsins; D020033:Protein Isoforms
keywords: Cell Differentiation; Neurodevelopment; Photoreceptor; Retina; Transcription Factor