Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Circadian clocks — the fall and rise of physiology

Abstract

Circadian clocks control the daily life of most light-sensitive organisms — from cyanobacteria to humans. Molecular processes generate cellular rhythmicity, and cellular clocks in animals coordinate rhythms through interaction (known as coupling). This hierarchy of clocks generates a complex, 24-hour temporal programme that is synchronized with the rotation of the Earth. The circadian system ensures anticipation and adaptation to daily environmental changes, and functions on different levels — from gene expression to behaviour. Circadian research is a remarkable example of interdisciplinarity, unravelling the complex mechanisms that underlie a ubiquitous biological programme. Insights from this research will help to optimize medical diagnostics and therapy, as well as adjust social and biological timing on the individual level.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The basic concept of the 'transcriptional–translational autoregulatory negative feedback loop'.
Figure 2: Model of the Synechococcus elongatus circadian clock.
Figure 3: Inputs and outputs of the clock.

References

  1. De Mairan, J. J. d'Ortous. Observation botanique. Histoire de l'Academie Royale des Science 35–36 (1729) (in French).

    Google Scholar 

  2. Duhamel Du Monceau, H. L. in La Physique des Arbres. (H. L. Guerin & L. F. Delatour, Paris, 1759) (in French).

    Google Scholar 

  3. Zinn, J. G. Über das Schlafen der Pflanzen. Hamburgisches Magazin 22, 40–50 (1759) (in German).

    Google Scholar 

  4. De Candolle, A. P. in Physiologie végétale (Bechet Jeune, Paris, 1832) (in French).

    Google Scholar 

  5. Richter, C. P. A behavioristic study of the activity of the rat. Comp. Psychol. Monogr. 1, 1–55 (1922).

    Google Scholar 

  6. Wever, R. in The Circadian System of Man (Springer, Berlin Heidelberg New York, 1979).

    Book  Google Scholar 

  7. Bünning, E. Über die Erblichkeit der Tagesperiodizität bei den Phaseolus Blättern. Jahrbücher für wissenschaftliche Botanik 81, 411–418 (1932) (in German).

    Google Scholar 

  8. Biological Clocks. Cold Spring Harb. Symp. Quant. Biol. 25 (1960).

  9. Pittendrigh, C. S. Circadian rhythms and the circadian organization of living systems. Cold Spring Harb. Symp. Quant. Biol. 25, 159–184 (1960).

    CAS  Article  Google Scholar 

  10. Brown, F. A. J. Response to pervasive geophysical factors and the biological clock problem. Cold Spring Harb. Symp.Quant. Biol. 25, 57–72 (1960).

    Article  Google Scholar 

  11. Halberg, F., Halberg, E., Barnum, C. P. & Bittner, J. J. (eds) Physiologic 24-hour Periodicity in Human Beings and Mice, the Lighting Regimen and Daily Routine. (AAAS Press, Washington DC, 1959).

    Google Scholar 

  12. von Frisch, K. The Dancing Bees (Methuen and Co., London, 1953).

    Google Scholar 

  13. Kramer, G. Experiments on bird orientation. Ibis (Lond. 1859) 94, 265–285 (1952).

    Article  Google Scholar 

  14. Hoffmann, K. Experimental manipulation of the orientational clock in birds. Cold Spring Harb. Symp. Quant. Biol. 25, 379–387 (1960).

    CAS  Article  Google Scholar 

  15. Hastings, J. W. & Sweeney, B. M. On the mechanism of temperature independence in a biological clock. Proc. Natl Acad. Sci. USA 43, 804–811 (1957).

    CAS  Article  Google Scholar 

  16. Richter, C. P. Inherent 24-hour and lunar clocks of a primate — the squirrel monkey. Comp. Behav. Biol. 1, 305–332 (1968).

    Google Scholar 

  17. Pittendrigh, C. S. & Daan, S. A functional analysis of circadian pacemakers in noctural rodents: I.-V. (the five papers make up one issue with alternating authorship). J. Comp. Physiol. A 106, 223–355 (1976).

    Article  Google Scholar 

  18. Daan, S. et al. Assembling a clock for all seasons: are M and E oscillators in the genes? J. Biol. Rhythms 16, 105–116 (2001).

    CAS  Article  Google Scholar 

  19. Mitsui, A., Cao, S., Takahashi, A. & Arai, T. Growth synchrony and cellular parameters of unicellular nitrogen-fixing marine cyanobacterium, Synechococcus sp. strain Miami BG 043511 under continuous illumination. Plant Physiol. 69, 1–8 (1987).

    CAS  Article  Google Scholar 

  20. Nishiitsutsuji-Uwo, J. & Pittendrigh, C. S. Central nervous system control of circadian rhytmicity in the cockroach. II. The optic lobes, locus of the driving oscillator? Zeitschrift der vergleichenden Physiologie 58, 14–46 (1968).

    Article  Google Scholar 

  21. Eskin, A. Identification and physiology of circadian pacemaker. Fed. Proc. 38, 2570–2572 (1979).

    CAS  PubMed  Google Scholar 

  22. Gaston, S. & Menaker, M. Pineal function. The biological clock in the sparrow. Science 160, 1125 (1968).

  23. Moore, R. Y. & Eichler, V. B. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 42, 201–206 (1972).

    CAS  Article  Google Scholar 

  24. Stephan, F. K. & Zucker, I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc. Natl Acad. Sci. USA 69, 1583–1586 (1972).

    CAS  Article  Google Scholar 

  25. Zimmermann, N. H. & Menaker, M. The pineal gland: a pacemaker within the circadian system of the house sparrow. Proc. Natl Acad. Sci. USA 76, 999–1003 (1979).

    Article  Google Scholar 

  26. Ralph, M. R., Foster, R. G., Davis, F. C. & Menaker, M. Transplanted suprachiasmatic nucleus determines circadian period. Science 247, 975–978 (1990).

    CAS  Article  Google Scholar 

  27. Rothman, B. & Strumwasser, F. J. Phase shifting the circadian rhythm of neuronal acitivty in the isolated Aplysia eye with puromycin and cycloheximide. J. Gen. Physiol. 68, 359–384 (1976).

    CAS  Article  Google Scholar 

  28. Takahashi, J. S., Hamm, H. & Menaker, M. Circadian rhythms of melatonin release from individual superfused chicken pineal glands in vitro. Proc. Natl Acad. Sci. USA 77, 2319–2322 (1980).

    CAS  Article  Google Scholar 

  29. Groos, G. A. & Hendriks, J. Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro. Neurosci. Lett. 34, 283–288 (1982).

    CAS  Article  Google Scholar 

  30. Andrews, R. V. & Folk, J. E. Circadian metabolic patterns in cultured hamster adrenal glands. Comp. Biochem. Physiol. 11, 393–409 (1964).

    CAS  Article  Google Scholar 

  31. Langer, R. & Rensing, L. Circadian rhythms of oxygen consumption in rat liver suspension culture: changes of pattern. Z. Naturforsch. B 27, 1117–1118 (1972).

    Article  Google Scholar 

  32. Pohl, R. Tagesrhythmus in phototaktischem Verhalten der Euglena gracilis. Z. Naturforsch. B 3, 367–374 (1948) (in German).

    Article  Google Scholar 

  33. Takahashi, J. S. Cellular basis of circadian rhythms in the avian pineal. in Comparative Aspects of Circadian Clocks (eds Hiroshige, T. & Honma, K.) 3–15 (Hokkaido University Press, Sapporo, 1987).

    Google Scholar 

  34. Michel, S., Geusz, M. E., Zaritsky, J. J. & Block, G. D. Circadian rhythm in membrane conductance expressed in isolated neurons. Science 259, 239–241 (1993).

    CAS  Article  Google Scholar 

  35. Welsh, D. K., Logothetis, D. E., Meister, M. & Reppert, S. M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14, 697–706 (1995).

    CAS  Article  Google Scholar 

  36. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    CAS  Article  Google Scholar 

  37. Brandes, C. et al. Novel features of Drosophila period transcription revealed by real-time luciferase reporting. Neuron 16, 687–692 (1996).

    CAS  Article  Google Scholar 

  38. Yamazaki, S. et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 288, 682–685 (2000).

    CAS  Article  Google Scholar 

  39. Welsh, D. K., Yoo, S. H., Lui, A. C., Takahashi, J. S. & Kay, S. A. Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr. Biol. 14, 2289–2295 (2004).

    CAS  Article  Google Scholar 

  40. Konopka, R. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971).

    CAS  Article  Google Scholar 

  41. Bargiello, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioural rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).

    CAS  Article  Google Scholar 

  42. Reddy, P. et al. Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell 38, 701–710 (1984).

    CAS  Article  Google Scholar 

  43. Hardin, P. E., Hall, J. C. & Rosbash, M. Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536–540 (1990).

    CAS  Article  Google Scholar 

  44. Young, M. W. & Kay, S. A. Time zones: a comparative genetics of circadian clocks. Nature Rev. Genet. 2, 702–715 (2001).

    CAS  Article  Google Scholar 

  45. Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–491 (2000).

    CAS  Article  Google Scholar 

  46. Roenneberg, T. & Merrow, M. Circadian light input: omnes viae Romam ducunt. Curr. Biol. 10, R742–R745 (2000).

    CAS  Article  Google Scholar 

  47. Roenneberg, T. & Merrow, M. The network of time: understanding the molecular circadian system. Curr. Biol. 13, R198–R207 (2003).

    CAS  Article  Google Scholar 

  48. Nakajima, M. et al. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308, 414–415 (2005).

    CAS  Article  Google Scholar 

  49. Roenneberg, T. & Merrow, M. Circadian clocks: translation lost. Curr. Biol. 15, R470–R473 (2005).

    CAS  Article  Google Scholar 

  50. Aschoff, J. Circadian rhythms: influences of internal and external factors on the period measured under constant conditions. Z. Tierpsychol. 49, 225–249 (1979).

    CAS  Article  Google Scholar 

  51. Winfree, A. T. The Geometry of Biological Time (Springer, New York, 1980).

    Book  Google Scholar 

  52. Daan, S. & Aschoff, J. in Handbook of Behavioral Neurobiology (eds Takahashi, J. S., Turek, F. W. & Moore, R. Y.) 7–43 (Kluwer, New York, 2001).

    Book  Google Scholar 

  53. Roenneberg, T., Dragovic, Z. & Merrow, M. Demasking biological oscillators: properties and principles of entrainment exemplified by the Neurospora circadian clock. Proc. Natl Acad. Sci. USA 102, 7742–7747 (2005).

    CAS  Article  Google Scholar 

  54. Crosthwaite, S. K., Loros, J. J. & Dunlap, J. C. Light-induced resetting of a circadian clock is mediated by a rapid increase in frequency transcript. Cell 81, 1003–1012 (1995).

    CAS  Article  Google Scholar 

  55. Albrecht, U., Sun, Z. S., Lee, C. C., Eichele, G. & McLean, V. M. A differential response of two putative mammalian circadian regulators, mper1 and mper2, to light. Cell 91, 1055–1064 (1997).

    CAS  Article  Google Scholar 

  56. Tan, Y., Dragovic, Z., Roenneberg, T. & Merrow, M. Entrainment of the circadian clock: translational and post-translational control as key elements. Curr. Biol. 14, 433–438 (2004).

    CAS  Article  Google Scholar 

  57. Freedman, M. S. et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284, 502–504 (1999).

    CAS  Article  Google Scholar 

  58. Hattar, S., Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002).

    CAS  Article  Google Scholar 

  59. Xu, Y. et al. Functional consequences of a CKId mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).

    CAS  Article  Google Scholar 

  60. Roenneberg, T. et al. A marker for the end of adolescence. Curr. Biol. 14, R1038–R1039 (2004).

    CAS  Article  Google Scholar 

  61. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    CAS  Article  Google Scholar 

  62. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    CAS  Article  Google Scholar 

  63. Akhtar, R. A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2001).

    Article  Google Scholar 

  64. Pittendrigh, C. S. On temperature independence in the clock controlling emergence time in Drosophila. Proc. Natl. Acad Sci. USA 40, 1018–1029 (1954).

    CAS  Article  Google Scholar 

  65. Aschoff, J. & Wever, R. Spontanperiodik des Menschen bei Ausschluss aller Zeitgeber. Naturwissenschaften 15, 337–342 (1962) (in German).

    Article  Google Scholar 

  66. Aschoff, J., Gerecke, U. & Wever, R. Desynchronization of human circadian rhythms. Jap. J. Physiol. 17, 450–457 (1967).

    CAS  Article  Google Scholar 

  67. Feldman, J. F. & Hoyle, M. N. Isolation of circadian clock mutants of Neurospora crassa. Genetics 75, 605–613 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mitsui, A. et al. Strategy by which nitrogen-fixing unicellular cyanobacteria grow phototrophically. Nature 323, 720–733 (1986).

    CAS  Article  Google Scholar 

  69. Roenneberg, T. & Morse, D. Two circadian oscillators in one cell. Nature 362, 362–364 (1993).

    Article  Google Scholar 

  70. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994).

    CAS  Article  Google Scholar 

  71. Hunter-Ensor, M., Ousley, A. & Sehgal, A. Regulation of the Drosophila protein Timeless suggests a mechanism for resetting the circadian clock by light. Cell 84, 677–685 (1996).

    CAS  Article  Google Scholar 

  72. Darlington, T. K. et al. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, 1599–1603 (1998).

    CAS  Article  Google Scholar 

  73. Somers, D. E., Webb, A. A., Pearson, M. & Kay, S. A. The short-period mutant, toc1–1, alters circadian clock regulation of multiple outputs throughout development in Arabidopsis thaliana. Development 125, 485–494 (1998).

    CAS  Google Scholar 

  74. Yan, O. Y. et al. Resonating circadian clocks enhance fitness in cyanobacteria. Proc. Natl Acad. Sci. USA 95, 8660–8664 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

We thank Serge Daan and Anna Wirz-Justice for their helpful comments. Our work is supported by the Deutsche Forschungsgemeinschaft, the Dr Meyer-Struckmann-Stiftung and by the European Union (BrainTime).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Till Roenneberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

mPer1

mPer2

per

Swiss-Prot

KaiA

KaiB

KaiC

TIMELESS

FURTHER INFORMATION

Till Roenneberg's laboratory

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Roenneberg, T., Merrow, M. Circadian clocks — the fall and rise of physiology. Nat Rev Mol Cell Biol 6, 965–971 (2005). https://doi.org/10.1038/nrm1766

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1766

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing