The orphan nuclear receptor RORα regulates circadian transcription of the mammalian core-clock Bmal1

The PAS (PER-ARNT-SIM) helix-loop-helix transcription factor BMAL1 (also known as MOP3) is an essential component of the circadian pacemaker in mammals. Here we show that the retinoic acid receptor–related orphan receptor RORα (NR1F1) directly activates transcription of Bmal1 through two conserved RORα response elements that are required for cell-autonomous transcriptional oscillation of Bmal1 mRNA. Positive involvement of RORα in generation of the Bmal1 circadian oscillation was verified by behavioral analyses of RORα-deficient staggerer mice that showed aberrant locomotor activity and unstable rhythmicity. In cultured cells, loss of endogenous RORα protein resulted in a dampened circadian rhythm of Bmal1 transcription, further indicating that RORα is a functional component of the cell-autonomous core circadian clock. These results indicate that RORα acts to promote Bmal1 transcription, thereby maintaining a robust circadian rhythm.

[1]  F. Fleury-Olela,et al.  Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. , 2000, Genes & development.

[2]  Paolo Sassone-Corsi,et al.  A Web of Circadian Pacemakers , 2002, Cell.

[3]  Yang Shi,et al.  Mammalian RNAi for the masses. , 2003, Trends in genetics : TIG.

[4]  E. Nishida,et al.  Control of Intracellular Dynamics of Mammalian Period Proteins by Casein Kinase I ε (CKIε) and CKIδ in Cultured Cells , 2002, Molecular and Cellular Biology.

[5]  Ueli Schibler,et al.  Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts , 2000, Current Biology.

[6]  F. Conquet,et al.  Disruption of retinoid‐related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice , 1998, The EMBO journal.

[7]  J. Takahashi,et al.  Stopping time: the genetics of fly and mouse circadian clocks. , 2001, Annual review of neuroscience.

[8]  John B. Hogenesch,et al.  Mop3 Is an Essential Component of the Master Circadian Pacemaker in Mammals , 2000, Cell.

[9]  B. Birren,et al.  Disruption of the nuclear hormone receptor RORα in staggerer mice , 1996, Nature.

[10]  M. W. Young,et al.  A light‐independent oscillatory gene mPer3 in mouse SCN and OVLT , 1998, The EMBO journal.

[11]  S. Kurebayashi,et al.  The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. , 2001, Progress in nucleic acid research and molecular biology.

[12]  Y Sakaki,et al.  Resetting central and peripheral circadian oscillators in transgenic rats. , 2000, Science.

[13]  Michael Menaker,et al.  Circadian Photoreception , 2003, Science.

[14]  A. B. Reddy,et al.  A clockwork web: circadian timing in brain and periphery, in health and disease , 2003, Nature Reviews Neuroscience.

[15]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[16]  S. Kliewer,et al.  Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. , 1994, Molecular endocrinology.

[17]  E. Maywood,et al.  mCRY 1 and mCRY 2 Are Essential Components of the Negative Limb of the Circadian Clock Feedback Loop to coordinated circadian outputs , 1999 .

[18]  L. Miraglia,et al.  A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock , 2004, Neuron.

[19]  S. Honma,et al.  Bidirectional role of orphan nuclear receptor RORα in clock gene transcriptions demonstrated by a novel reporter assay system , 2004, FEBS letters.

[20]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[21]  S. Ishii,et al.  Generation of Ski-knockdown mice by expressing a long double-strand RNA from an RNA polymerase II promoter. , 2003, Genes & development.

[22]  C. Chauvet,et al.  Retinoic acid receptor-related orphan receptor (ROR) alpha4 is the predominant isoform of the nuclear receptor RORalpha in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells. , 2002, The Biochemical journal.

[23]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[24]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.

[25]  F. Dilworth,et al.  Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription , 2001, Oncogene.

[26]  Haruhiko Soma,et al.  Transcriptional oscillation of canonical clock genes in mouse peripheral tissues , 2004, BMC Molecular Biology.

[27]  V. Giguère,et al.  Orphan nuclear receptors: from gene to function. , 1999 .

[28]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[29]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.

[30]  M. Geiser,et al.  X-Ray Structure of the hROR LBD at 1 . 63 Å : Structural and Functional Data that Cholesterol or a Cholesterol Derivative Is the Natural Ligand of ROR , 2002 .

[31]  P. Hardin,et al.  Central and peripheral circadian oscillator mechanisms in flies and mammals. , 2002, Journal of cell science.

[32]  U. Schibler,et al.  A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells , 1998, Cell.

[33]  E. Nishida,et al.  Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. , 2000, Genes & development.

[34]  M. Ikuta,et al.  Hypoxia-induced Activation of the Retinoic Acid Receptor-related Orphan Receptor α4 Gene by an Interaction between Hypoxia-inducible Factor-1 and Sp1* , 2004, Journal of Biological Chemistry.

[35]  D. Lavery,et al.  The role of the transcriptional activator protein DBP in circadian liver gene expression , 1992, Journal of Cell Science.

[36]  J. Pouysségur,et al.  The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1. , 2004, The Biochemical journal.

[37]  M. Geiser,et al.  X-Ray Structure of the hRORα LBD at 1.63 Å , 2002 .

[38]  J. Dunlap.  Molecular Bases for Circadian Clocks , 1999, Cell.

[39]  B. Birren,et al.  Correction: Disruption of the nuclear hormone receptor RORα in staggerer mice (Nature Journal (1996) 379 (736-739)) , 1996 .

[40]  P. Roach,et al.  Circadian rhythm in hepatic low-density-lipoprotein (LDL)-receptor expression and plasma LDL levels. , 1994, The Biochemical journal.

[41]  E. Ikonen,et al.  How cells handle cholesterol. , 2000, Science.

[42]  S. Kay,et al.  Time zones: a comparative genetics of circadian clocks , 2001, Nature Reviews Genetics.

[43]  L. Huang,et al.  Erythropoietin: a model system for studying oxygen-dependent gene regulation. , 1998, The Journal of experimental biology.

[44]  Kai-Florian Storch,et al.  Extensive and divergent circadian gene expression in liver and heart , 2002, Nature.