, Volume 113, Issue 3, pp 103–112 | Cite as

The mammalian circadian timing system: from gene expression to physiology

  • Frédéric Gachon
  • Emi Nagoshi
  • Steven A. Brown
  • Juergen Ripperger
  • Ueli SchiblerEmail author


Many physiological processes in organisms from bacteria to man are rhythmic, and some of these are controlled by self-sustained oscillators that persist in the absence of external time cues. Circadian clocks are perhaps the best characterized biological oscillators and they exist in virtually all light-sensitive organisms. In mammals, they influence nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrinology, body temperature, renal activity, physiology of the gastro-intestinal tract, and hepatic metabolism. The master pacemaker is located in the suprachiasmatic nuclei, two small groups of neurons in the ventral part of the hypothalamus. However, most peripheral body cells contain self-sustained circadian oscillators with a molecular makeup similar to that of SCN (suprachiasmatic nucleus) neurons. This organization implies that the SCN must synchronize countless subsidiary oscillators in peripheral tissues, in order to coordinate cyclic physiology. In this review, we will discuss some recent studies on the structure and putative functions of the mammalian circadian timing system, but we will also point out some apparent inconsistencies in the currently publicized model for rhythm generation.


Circadian Clock Clock Gene Period Length Circadian Oscillator Peripheral Clock 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Nicolas Roggli for the artwork. Research from our own laboratory discussed in this review has been supported by Swiss National Science Foundation (grant to U.S.), the State of Geneva, the NCCR program “Frontiers in Genetics,” the Bonnizzi Theler Stiftung, and the Louis Jeantet Foundation of Medicine. F.G. received a postdoctoral fellowship from the Fondation pour la Recherche Médicale (France).


  1. Akashi M, Nishida E (2000) Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev 14:645–649PubMedGoogle Scholar
  2. Akhtar RA, Reddy AB, Maywood ES, Clayton JD, King VM, Smith AG, Gant TW, Hastings MH, Kyriacou CP (2002) Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 12:540–550CrossRefPubMedGoogle Scholar
  3. Albrecht U, Eichele G (2003) The mammalian circadian clock. Curr Opin Genet Dev 13:271–277CrossRefPubMedGoogle Scholar
  4. Baggs JE, Green CB (2003) Nocturnin, a deadenylase in Xenopus laevis retina: a mechanism for posttranscriptional control of circadian-related mRNA. Curr Biol 13:189–198CrossRefPubMedGoogle Scholar
  5. Ballauff A, Rascher W, Tolle HG, Wember T, Manz F (1991) Circadian rhythms of urine osmolality and renal excretion rates of solutes influencing water metabolism in 21 healthy children. Miner Electrolyte Metab 17:377–382PubMedGoogle Scholar
  6. Balsalobre A, Damiola F, Schibler U (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93:929–937CrossRefPubMedGoogle Scholar
  7. Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U (2000a) Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289:2344–2347CrossRefPubMedGoogle Scholar
  8. Balsalobre A, Marcacci L, Schibler U (2000b) Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr Biol 10:1291–1294CrossRefPubMedGoogle Scholar
  9. Bartness TJ, Powers JB, Hastings MH, Bittman EL, Goldman BD (1993) The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? J Pineal Res 15:161–190PubMedGoogle Scholar
  10. Berman-Frank I, Lundgren P, Chen YB, Kupper H, Kolber Z, Bergman B, Falkowski P (2001) Segregation of nitrogen fixation and oxygenic photosynthesis in the marine cyanobacterium Trichodesmium. Science 294:1534–1537CrossRefPubMedGoogle Scholar
  11. Berson DM (2003) Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci 26:314–320CrossRefPubMedGoogle Scholar
  12. Bondy SC, Naderi S (1994) Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species. Biochem Pharmacol 48:155–159Google Scholar
  13. Brown SA, Zumbrunn G, Fleury-Olela F, Preitner N, Schibler U (2002) Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr Biol 12:1574–1583CrossRefPubMedGoogle Scholar
  14. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U (2000) Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 14:2950–2961CrossRefPubMedGoogle Scholar
  15. Duffield GE, Best JD, Meurers BH, Bittner A, Loros JJ, Dunlap JC (2002) Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol 12:551–557CrossRefPubMedGoogle Scholar
  16. Dunlap JC (1999) Molecular bases for circadian clocks. Cell 96:271–290CrossRefPubMedGoogle Scholar
  17. Eide EJ, Virshup DM (2001) Casein kinase I: another cog in the circadian clockworks. Chronobiol Int 18:389–398CrossRefPubMedGoogle Scholar
  18. Eide EJ, Vielhaber EL, Hinz WA, Virshup DM (2002) The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. J Biol Chem 277:17248–17254CrossRefPubMedGoogle Scholar
  19. Ellis RJ (2001) Macromolecular crowding: an important but neglected aspect of the intracellular environment. Curr Opin Struct Biol 11:114–119CrossRefPubMedGoogle Scholar
  20. Etchegaray JP, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182CrossRefPubMedGoogle Scholar
  21. Freedman MS, Lucas RJ, Soni B, von Schantz M, Munoz M, David-Gray Z, Foster R (1999) Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284:502–504CrossRefPubMedGoogle Scholar
  22. Froehlich AC, Pregueiro A, Lee K, Denault D, Colot H, Nowrousian M, Loros JJ, Dunlap JC (2003) The molecular workings of the Neurospora biological clock. Novartis Found Symp 253:184–198CrossRefPubMedGoogle Scholar
  23. Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50CrossRefPubMedGoogle Scholar
  24. Furukawa T, Manabe S, Watanabe T, Sehata S, Sharyo S, Okada T, Mori Y (1999) Daily fluctuation of hepatic P450 monooxygenase activities in male rats is controlled by the suprachiasmatic nucleus but remains unaffected by adrenal hormones. Arch Toxicol 73:367–372CrossRefPubMedGoogle Scholar
  25. Gachon F, Fonjallaz P, Damiola F, Gos P, Kodama T, Zakany J, Duboule D, Petit B, Tafti M, Schibler U (2004) The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev 18:1397–1412CrossRefPubMedGoogle Scholar
  26. Gerkema MP, van der Leest F (1991) Ongoing ultradian activity rhythms in the common vole, Microtus arvalis, during deprivations of food, water and rest. J Comp Physiol [A] 168:591–597Google Scholar
  27. Golden SS (2003) Timekeeping in bacteria: the cyanobacterial circadian clock. Curr Opin Microbiol 6:535–540CrossRefPubMedGoogle Scholar
  28. Hannibal J (2002) Neurotransmitters of the retino-hypothalamic tract. Cell Tissue Res 309:73–88CrossRefPubMedGoogle Scholar
  29. Hardin PE, Hall JC, Rosbash M (1990) Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343:536–540CrossRefPubMedGoogle Scholar
  30. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi JC et al (2002) The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109:497–508CrossRefPubMedGoogle Scholar
  31. Harmer SL, Hogenesch JB, Straume M, Chang HS, Han B, Zhu T, Wang X, Kreps JA, Kay SA (2000) Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290:2110–2113CrossRefPubMedGoogle Scholar
  32. Harms E, Young MW, Saez L (2003) CK1 and GSK3 in the Drosophila and mammalian circadian clock. Novartis Found Symp 253:267–277CrossRefPubMedGoogle Scholar
  33. Hattar S, Lucas RJ, Mrosovsky N, Thompson S, Douglas RH, Hankins MW, Lem J, Biel M, Hofmann F, Foster RG, Yau KW (2003) Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424:75–81CrossRefGoogle Scholar
  34. Hirota T, Okano T, Kokame K, Shirotani-Ikejima H, Miyata T, Fukada Y (2002) Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured rat-1 fibroblasts. J Biol Chem 277:44244–44251CrossRefPubMedGoogle Scholar
  35. Hoppensteadt FC, Keller JB (1976) Synchronization of periodical cicada emergences. Science 194:335–337PubMedGoogle Scholar
  36. Ishikawa K, Shimazu T (1976) Daily rhythms of glycogen synthetase and phosphorylase activities in rat liver: influence of food and light. Life Sci 19:1873–1878CrossRefPubMedGoogle Scholar
  37. Izumo M, Johnson CH, Yamazaki S (2003) Circadian gene expression in mammalian fibroblasts revealed by real-time luminescence reporting: temperature compensation and damping. Proc Natl Acad Sci USA 100:16089–16094CrossRefPubMedGoogle Scholar
  38. Jin X, Shearman LP, Weaver DR, Zylka MJ, de Vries GJ, Reppert SM (1999) A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96:57–68CrossRefPubMedGoogle Scholar
  39. King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL et al (1997) Positional cloning of the mouse circadian clock gene. Cell 89:641–653CrossRefPubMedGoogle Scholar
  40. Klevecz RR, Bolen J, Forrest G, Murray DB (2004) A genomewide oscillation in transcription gates DNA replication and cell cycle. Proc Natl Acad Sci USA 101:1200–1205CrossRefPubMedGoogle Scholar
  41. Lavery DJ, Lopez-Molina L, Margueron R, Fleury-Olela F, Conquet F, Schibler U, Bonfils C (1999) Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Mol Cell Biol 19:6488–6499PubMedGoogle Scholar
  42. Le Minh N, Damiola F, Tronche F, Schutz G, Schibler U (2001) Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J 20:7128–7136CrossRefPubMedGoogle Scholar
  43. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM (2001) Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107:855–867CrossRefPubMedGoogle Scholar
  44. Lee C, Weaver DR, Reppert SM (2004) Direct association between mouse PERIOD and CKIepsilon is critical for a functioning circadian clock. Mol Cell Biol 24:584–594CrossRefPubMedGoogle Scholar
  45. Leloup JC, Goldbeter A (2003) Toward a detailed computational model for the mammalian circadian clock. Proc Natl Acad Sci USA 100:7051–7056CrossRefPubMedGoogle Scholar
  46. Lin JM, Kilman VL, Keegan K, Paddock B, Emery-Le M, Rosbash M, Allada R (2002) A role for casein kinase 2alpha in the Drosophila circadian clock. Nature 420:816–820CrossRefPubMedGoogle Scholar
  47. Lincoln GA, Andersson H, Loudon A (2003) Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis. J Endocrinol 179:1–13PubMedGoogle Scholar
  48. Liu C, Weaver DR, Strogatz SH, Reppert SM (1997) Cellular construction of a circadian clock: period determination in the suprachiasmatic nuclei. Cell 91:855–860CrossRefPubMedGoogle Scholar
  49. Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, Ralph MR, Menaker M, Takahashi JS (2000) Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288:483–492CrossRefPubMedGoogle Scholar
  50. McNamara P, Seo SP, Rudic RD, Sehgal A, Chakravarti D, FitzGerald GA (2001) Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105:877–889CrossRefPubMedGoogle Scholar
  51. Murray DB, Roller S, Kuriyama H, Lloyd D (2001) Clock control of ultradian respiratory oscillation found during yeast continuous culture. J Bacteriol 183:7253–7259CrossRefPubMedGoogle Scholar
  52. Nawathean P, Rosbash M (2004) The doubletime and CKII kinases collaborate to potentiate Drosophila PER transcriptional repressor activity. Mol Cell 13:213–223CrossRefPubMedGoogle Scholar
  53. Ouyang Y, Andersson CR, Kondo T, Golden SS, Johnson CH (1998) Resonating circadian clocks enhance fitness in cyanobacteria. Proc Natl Acad Sci USA 95:8660–8664CrossRefPubMedGoogle Scholar
  54. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB (2002) Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109:307–320CrossRefPubMedGoogle Scholar
  55. Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, Pletcher MT, Sato TK, Wiltshire T, Andahazy M et al (2003) Melanopsin is required for non-image-forming photic responses in blind mice. Science 301:525–527CrossRefPubMedGoogle Scholar
  56. Pourquie O (2003) The segmentation clock: converting embryonic time into spatial pattern. Science 301:328–330CrossRefPubMedGoogle Scholar
  57. Preitner N, Damiola F, Luis Lopez M, Zakany J, Duboule D, Albrecht U, Schibler U (2002) The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110:251–260CrossRefPubMedGoogle Scholar
  58. Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW (1998) Double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94:83–95CrossRefPubMedGoogle Scholar
  59. Ralph MR, Foster RG, Davis FC, Menaker M (1990) Transplanted suprachiasmatic nucleus determines circadian period. Science 247:975–978PubMedGoogle Scholar
  60. Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941CrossRefPubMedGoogle Scholar
  61. Ripperger JA, Shearman LP, Reppert SM, Schibler U (2000) CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes Dev 14:679–689PubMedGoogle Scholar
  62. Roenneberg T, Merrow M (2003) The network of time: understanding the molecular circadian system. Curr Biol 13:R198–R207CrossRefPubMedGoogle Scholar
  63. Rutter J, Reick M, Wu LC, McKnight SL (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293:510–514CrossRefPubMedGoogle Scholar
  64. Sathyanarayanan S, Zheng X, Xiao R, Sehgal A (2004) Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116:603–615CrossRefPubMedGoogle Scholar
  65. Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 93:1563–1568CrossRefPubMedGoogle Scholar
  66. Schibler U, Ripperger J, Brown SA (2003) Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms 18:250–260CrossRefPubMedGoogle Scholar
  67. Shen H, Watanabe M, Tomasiewicz H, Rutishauser U, Magnuson T, Glass JD (1997) Role of neural cell adhesion molecule and polysialic acid in mouse circadian clock function. J Neurosci 17:5221–5229PubMedGoogle Scholar
  68. Silver R, LeSauter J, Tresco PA, Lehman MN (1996) A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382:810–813CrossRefPubMedGoogle Scholar
  69. Staiger D (2002) Circadian rhythms in Arabidopsis: time for nuclear proteins. Planta 214:334–344CrossRefPubMedGoogle Scholar
  70. Stanewsky R (2003) Genetic analysis of the circadian system in Drosophila melanogaster and mammals. J Neurobiol 54:111–147CrossRefPubMedGoogle Scholar
  71. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, Menaker M (2001) Entrainment of the circadian clock in the liver by feeding. Science 291:490–493CrossRefPubMedGoogle Scholar
  72. Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, Weitz CJ (2002) Extensive and divergent circadian gene expression in liver and heart. Nature 417:78–83CrossRefPubMedGoogle Scholar
  73. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptacek LJ, Fu YH (2001) An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome. Science 291:1040–1043CrossRefPubMedGoogle Scholar
  74. Tsuchiya Y, Akashi M, Nishida E (2003) Temperature compensation and temperature resetting of circadian rhythms in mammalian cultured fibroblasts. Genes Cells 8:713–720CrossRefPubMedGoogle Scholar
  75. Wang Y, Osterbur DL, Megaw PL, Tosini G, Fukuhara C, Green CB, Besharse JC (2001) Rhythmic expression of Nocturnin mRNA in multiple tissues of the mouse. BMC Dev Biol 1:9CrossRefPubMedGoogle Scholar
  76. Yagita K, Okamura H (2000) Forskolin induces circadian gene expression of rPer1, rPer2 and dbp in mammalian rat-1 fibroblasts. FEBS Lett 465:79–82CrossRefPubMedGoogle Scholar
  77. Yagita K, Tamanini F, van Der Horst GT, Okamura H (2001) Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292:278–281CrossRefPubMedGoogle Scholar
  78. Yamaguchi S, Isejima H, Matsuo T, Okura R, Yagita K, Kobayashi M, Okamura H (2003) Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302:1408–1412CrossRefPubMedGoogle Scholar
  79. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, Block GD, Sakaki Y, Menaker M, Tei H (2000) Resetting central and peripheral circadian oscillators in transgenic rats. Science 288:682–685CrossRefPubMedGoogle Scholar
  80. Yoo SH, Yamazaki S, Lowrey PL, Shimomura K, Ko CH, Buhr ED, Siepka SM, Hong HK, Oh WJ, Yoo OJ, et al (2004) PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci USA 101:5339–5346CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Frédéric Gachon
    • 1
  • Emi Nagoshi
    • 1
  • Steven A. Brown
    • 1
  • Juergen Ripperger
    • 1
  • Ueli Schibler
    • 1
    Email author
  1. 1.Department of Molecular Biology, Sciences IIIUniversity of GenevaGeneva-4Switzerland

Personalised recommendations