TABLE 5

RORα

Receptor nomenclature NR1F1
Receptor code 4.10.1:OR:1:F1
Other names RZRα, RORA
Molecular information Hs: 556aa, P35398 chr. 15q21-q221
Rn: 523aa, chr. 8q24
Mm: 523aa, P51448, chr. 9 D2,3
DNA binding
   Structure Monomer, homodimer
   HRE core sequence T/A A/T T/A C A/T A/GGGTCA (DR-2, half-site)
Partners MyoD1 (physical, functional): interaction mediated by the N-terminal activation domain of the bHLH protein, MyoD, and RORα 1 DNA-binding domain/C region4; Nm23-1 (physical)5; Nm23-2 (physical)5
Agonists Cholesterol, cholesterol sulfate6–8
Antagonists
Coactivators NCOA2, PPARBP, EP3004,9
Corepressors NCOR1, NCOR2,10 HR11
Biologically important isoforms RORα 1 {Hs, Rn}1,12; RORα 2 {Rn}1,12; RORα 3 {Rn}1,12; RORα 4 {Rn}1,12; the four RORα isoforms differ in their N-terminal domain and exhibit differential DNA binding preferences1,12
Tissue distribution Lung, muscle, brain (retinal ganglion cells, cerebellum, thalamus, suprachiasmatic nucleus), heart, leukocytes, spleen, liver, ovary, testis, cartilage, skin, lens, intestinal epithelium {Hs, Mm, Rn} [Northern, in situ hybridization]1,4,13–19
Functional assays
Main target genes Activated: N-Myc {Hs},20 ApoA5 {Hs},21 laminin B1 {Hs},22 Bmal1 {Mm},23,24 fibrinogen β {Hs},25 Rev-erbAα {Hs},26,27
Mutant phenotype The invalidation of RORα causes the stagger phenotype in the cerebellum; no apparent morphological effects on the thalamus, hypothalamus, retina, or regions in which RORα is expressed were detected; however, the pelage is significantly less dense and has growth difficulties when shaved {Mm} [knockout]3,16,28,29
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; bHLH, basic helix-loop-helix; PPARBP, PPAR-binding protein; HR, hairless

  • ↵1. Giguere V, Tini M, Flock G, Ong E, Evans RM, and Otulakowski G (1994) Isoform-specific amino-terminal domains dictate DNA-binding properties of RORα, a novel family of orphan hormone nuclear receptors. Genes Dev 8: 538-553

  • ↵2. McBroom LD, Flock G, and Giguere V (1995) The nonconserved hinge region and distinct amino-terminal domains of the ROR α orphan nuclear receptor isoforms are required for proper DNA bending and RORα -DNA interactions. Mol Cell Biol 15: 796-808

  • ↵3. Matysiak-Scholze U and Nehls M (1997) The structural integrity of RORα isoforms is mutated in staggerer mice: cerebellar coexpression of RORα 1 and RORα 4. Genomics 43: 78-84

  • ↵4. Medvedev A, Yan ZH, Hirose T, Giguere V, and Jetten AM (1996) Cloning of a cDNA encoding the murine orphan receptor RZR/RORγ and characterization of its response element. Gene 181: 199-206

  • ↵5. Lau P, Bailey P, Dowhan DH, and Muscat GE (1999) Exogenous expression of a dominant negative RORα 1 vector in muscle cells impairs differentiation: RORα 1 directly interacts with p300 and myoD. J Biol Chem 274: 411-420

  • ↵6. Paravicini G, Steinmayr M, Andre E, and Becker-Andre M (1996) The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily. Biochem Biophys Res Commun 227: 82-87

  • ↵7. Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, and Fournier B (2002) X-ray structure of the hRORα LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure (Camb) 10: 1697-1707

  • ↵8. Bitsch F, Aichholz R, Kallen J, Geisse S, Fournier B, and Schlaeppi JM (2003) Identification of natural ligands of retinoic acid receptor-related orphan receptor α ligand-binding domain expressed in Sf9 cells—a mass spectrometry approach. Anal Biochem 323: 139-149

  • ↵9. Kallen J, Schlaeppi JM, Bitsch F, Delhon I, and Fournier B (2004) Crystal structure of the human RORα ligand binding domain in complex with cholesterol sulfate at 2.2 A. J Biol Chem 279: 14033-14038

  • ↵10. Atkins GB, Hu X, Guenther MG, Rachez C, Freedman LP, and Lazar MA (1999) Coactivators for the orphan nuclear receptor RORα. Mol Endocrinol 13: 1550-1557

  • ↵11. Harding HP, Atkins GB, Jaffe AB, Seo WJ, and Lazar MA (1997) Transcriptional activation and repression by RORα, an orphan nuclear receptor required for cerebellar development. Mol Endocrinol 11: 1737-1746

  • ↵12. Moraitis AN, Giguere V, and Thompson CC (2002) Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol Cell Biol 22: 6831-6841

  • ↵13. Becker-Andre M, Andre E, and DeLamarter JF (1993) Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. Biochem Biophys Res Commun 194: 1371-1379

  • ↵14. Tini M, Fraser RA, and Giguere V (1995) Functional interactions between retinoic acid receptor-related orphan nuclear receptor (RORα) and the retinoic acid receptors in the regulation of the γ F-crystallin promoter. J Biol Chem 270: 20156-20161

  • ↵15. Andre E, Conquet F, Steinmayr M, Stratton SC, Porciatti V, and Becker-Andre M (1998) Disruption of retinoid-related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO (Eur Mol Biol Organ) J 17: 3867-3877

  • ↵16. Steinmayr M, Andre E, Conquet F, Rondi-Reig L, Delhaye-Bouchaud N, Auclair N, Daniel H, Crepel F, Mariani J, Sotelo C, et al. (1998) staggerer phenotype in retinoid-related orphan receptor α -deficient mice. Proc Natl Acad Sci USA 95: 3960-3965

  • ↵17. Hamilton BA, Frankel WN, Kerrebrock AW, Hawkins TL, FitzHugh W, Kusumi K, Russell LB, Mueller KL, van Berkel V, Birren BW, et al. (1996) Disruption of the nuclear hormone receptor RORα in staggerer mice. Nature (Lond) 379: 736-739

  • ↵18. Bordji K, Grillasca JP, Gouze JN, Magdalou J, Schohn H, Keller JM, Bianchi A, Dauca M, Netter R, and Terlain B (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) α and γ and retinoid Z receptor in cartilage. PPARγ activation modulates the effects of interleukin-1β on rat chondrocytes. J Biol Chem 275: 12243-12250

  • ↵19. Meyer T, Kneissel M, Mariani J, and Fournier B (2000) In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism. Proc Natl Acad Sci USA 97: 9197-9202

  • ↵20. Dussault I and Giguere V (1997) Differential regulation of the N-myc proto-oncogene by RORα and RVR, two orphan members of the superfamily of nuclear hormone receptors. Mol Cell Biol 17: 1860-1867

  • ↵21. Genoux A, Dehondt H, Helleboid-Chapman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, and Fruchart JC (2005) Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORα. Arterioscler Thromb Vasc Biol 25: 1186-1192

  • ↵22. Matsui T (1996) Differential activation of the murine laminin B1 gene promoter by RARα, RORα, and AP-1. Biochem Biophys Res Commun 220: 405-410

  • ↵23. Nakajima Y, Ikeda M, Kimura T, Honma S, Ohmiya Y, and Honma K (2004) Bidirectional role of orphan nuclear receptor RORα in clock gene transcriptions demonstrated by a novel reporter assay system. FEBS Lett 565: 122-126

  • ↵24. Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, Naik KA, FitzGerald GA, Kay SA, and Hogenesch JB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43: 527-537

  • ↵25. Chauvet C, Bois-Joyeux B, Fontaine C, Gervois P, Bernard MA, Staels B, and Danan JL (2005) The gene encoding fibrinogen-β is a target for retinoic acid receptor-related orphan receptor α. Mol Endocrinol 19: 2517-2526

  • ↵26. Delerive P, Chin WW, and Suen CS (2002) Identification of Reverbα as a novel RORα target gene. J Biol Chem 277: 35013-35018

  • ↵27. Raspe E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, and Staels B (2002) Transcriptional regulation of human Rev-erbα gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor α. J Biol Chem 277: 49275-49281

  • ↵28. Dussault I, Fawcett D, Matthyssen A, Bader JA, and Giguere V (1998) Orphan nuclear receptor ROR α -deficient mice display the cerebellar defects of staggerer. Mech Dev 70: 147-153

  • ↵29. Sidman RL, Lane PW, and Dickie MM (1962) Staggerer, a new mutation in the mouse affecting the cerebellum. Science (Wash DC) 137: 610-612