Circadian rhythms from flies to human

Abstract

In this era of jet travel, our body 'remembers' the previous time zone, such that when we travel, our sleep–wake pattern, mental alertness, eating habits and many other physiological processes temporarily suffer the consequences of time displacement until we adjust to the new time zone. Although the existence of a circadian clock in humans had been postulated for decades, an understanding of the molecular mechanisms has required the full complement of research tools. To gain the initial insights into circadian mechanisms, researchers turned to genetically tractable model organisms such as Drosophila.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Assay of circadian activity rhythm in flies and mice.
Figure 2: Schematic diagrams showing anatomic features of Drosophila and rodent central oscillator.
Figure 3: Drosophila and mammalian circadian clock.

References

  1. 1

    Pittendrigh, C. S. Circadian systems. I. The driving oscillation and its assay in Drosophila pseudoobscura. Proc. Natl Acad. Sci. USA 58, 1762–1767 (1967).

    ADS  CAS  PubMed  Google Scholar 

  2. 2

    Shaw, P. J., Cirelli, C., Greenspan, R. J. & Tononi, G. Correlates of sleep and waking in Drosophila melanogaster. Science 287, 1834–1837 (2000).

    ADS  CAS  Google Scholar 

  3. 3

    Hendricks, J. C. et al. Rest in Drosophila is a sleep-like state. Neuron 25, 129–138 (2000).

    CAS  Google Scholar 

  4. 4

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

    ADS  CAS  Google Scholar 

  5. 5

    Handler, A. M. & Konopka, R. J. Transplantation of a circadian pacemaker in Drosophila. Nature 279, 236–238 (1979).

    ADS  CAS  Google Scholar 

  6. 6

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

    ADS  CAS  Google Scholar 

  7. 7

    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  Google Scholar 

  8. 8

    Baylies, M. K., Bargiello, T. A., Jackson, F. R. & Young, M. W. Changes in abundance or structure of the per gene product can alter periodicity of the Drosophila clock. Nature 326, 390–392 (1987).

    ADS  CAS  Google Scholar 

  9. 9

    Ewer, J., Frisch, B., Hamblen-Coyle, M. J., Rosbash, M. & Hall, J. C. Expression of the period clock gene within different cell types in the brain of Drosophila adults and mosaic analysis of these cells' influence on circadian behavioral rhythms. J. Neurosci. 12, 3321–3349 (1992).

    CAS  Google Scholar 

  10. 10

    Vosshall, L. B. & Young, M. W. Circadian rhythms in Drosophila can be driven by period expression in a restricted group of central brain cells. Neuron 15, 345–360 (1995).

    CAS  Google Scholar 

  11. 11

    Colot, H. V., Hall, J. C. & Rosbash, M. Interspecific comparison of the period gene of Drosophila reveals large blocks of non-conserved coding DNA. EMBO J. 7, 3929–3937 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Reppert, S. M., Tsai, T., Roca, A. L. & Sauman, I. Cloning of a structural and functional homolog of the circadian clock gene period from the giant silkmoth Antheraea pernyi. Neuron 13, 1167–1176 (1994).

    CAS  Google Scholar 

  13. 13

    Sauman, I. & Reppert, S. M. Circadian clock neurons in the silkmoth Antheraea pernyi: novel mechanisms of Period protein regulation. Neuron 17, 889–900 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Regier, J. C. et al. Evolution and phylogenetic utility of the period gene in Lepidoptera. Mol. Biol. Evol. 15, 1172–1182 (1998).

    CAS  Google Scholar 

  15. 15

    Toma, D. P., Bloch, G., Moore, D. & Robinson, G. E. Changes in period mRNA levels in the brain and division of labor in honey bee colonies. Proc. Natl Acad. Sci. USA 97, 6914–6919 (2000).

    ADS  CAS  PubMed  Google Scholar 

  16. 16

    Levine, J. D., Sauman, I., Imbalzano, M., Reppert, S. M. & Jackson, F. R. Period protein from the giant silkmoth Antheraea pernyi functions as a circadian clock element in Drosophila melanogaster. Neuron 15, 147–157 (1995).

    CAS  Google Scholar 

  17. 17

    Siwicki, K. K., Strack, S., Rosbash, M., Hall, J. C. & Jacklet, J. W. An antibody to the Drosophila period protein recognizes circadian pacemaker neurons in Aplysia and Bulla. Neuron 3, 51–58 (1989).

    CAS  Google Scholar 

  18. 18

    Siwicki, K. K., Schwartz, W. J. & Hall, J. C. An antibody to the Drosophila period protein labels antigens in the suprachiasmatic nucleus of the rat. J. Neurogenet. 8, 33–42 (1992).

    CAS  Google Scholar 

  19. 19

    Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606 (1994).

    ADS  CAS  Google Scholar 

  20. 20

    Vosshall, L. B., Price, J. L., Sehgal, A., Saez, L. & Young, M. W. Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263, 1606–1609 (1994).

    ADS  CAS  Google Scholar 

  21. 21

    Sehgal, A. et al. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 270, 808–810 (1995).

    ADS  CAS  Google Scholar 

  22. 22

    Gekakis, N. et al. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science 270, 811–815 (1995).

    ADS  CAS  Google Scholar 

  23. 23

    Hoffman, E. C. et al. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252, 954–958 (1991).

    ADS  CAS  PubMed  Google Scholar 

  24. 24

    Crews, S. T., Thomas, J. B. & Goodman, C. S. The Drosophila single-minded gene encodes a nuclear protein with sequence similarity to the per gene product. Cell 52, 143–151 (1988).

    CAS  Google Scholar 

  25. 25

    Huang, Z. J., Edery, I. & Rosbash, M. PAS is a dimerization domain common to Drosophila Period and several transcription factors. Nature 364, 259–262 (1993).

    ADS  CAS  Google Scholar 

  26. 26

    Hao, H., Allen, D. L. & Hardin, P. E. A circadian enhancer mediates PER-dependent mRNA cycling in Drosophila melanogaster. Mol. Cell. Biol. 17, 3687–3693 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Rutila, J. E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814 (1998).

    CAS  Google Scholar 

  29. 29

    Allada, R., White, N. E., So, W. V., Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998).

    CAS  Google Scholar 

  30. 30

    Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    ADS  CAS  Google Scholar 

  31. 31

    Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95 (1998).

    CAS  Google Scholar 

  33. 33

    Blau, J. & Young, M. W. Cycling vrille expression is required for a functional Drosophila clock. Cell 99, 661–671 (1999).

    CAS  Google Scholar 

  34. 34

    Martinek, S., Inonog, S., Manoukian, A. S. & Young, M. W. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769–779 (2001).

    CAS  Google Scholar 

  35. 35

    Kloss, B., Rothenfluh, A., Young, M. W. & Saez, L. Phosphorylation of PERIOD is influenced by cycling physical associations of DOUBLE-TIME, PERIOD, and TIMELESS in the Drosophila clock. Neuron 30, 699–706 (2001).

    CAS  Google Scholar 

  36. 36

    Rothenfluh, A., Young, M. W. & Saez, L. A TIMELESS-independent function for PERIOD proteins in the Drosophila clock. Neuron 26, 505–514 (2000).

    CAS  Google Scholar 

  37. 37

    Bao, S., Rihel, J., Bjes, E., Fan, J. Y. & Price, J. L. The Drosophila double-timeS mutation delays the nuclear accumulation of period protein and affects the feedback regulation of period mRNA. J. Neurosci. 21, 7117–7126 (2001).

    CAS  Google Scholar 

  38. 38

    Bae, K., Lee, C., Sidote, D., Chuang, K. Y. & Edery, I. Circadian regulation of a Drosophila homolog of the mammalian Clock gene: PER and TIM function as positive regulators. Mol. Cell. Biol. 18, 6142–6151 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lee, C., Bae, K. & Edery, I. The Drosophila CLOCK protein undergoes daily rhythms in abundance, phosphorylation, and interactions with the PER-TIM complex. Neuron 21, 857–867 (1998).

    CAS  Google Scholar 

  40. 40

    Glossop, N. R., Lyons, L. C. & Hardin, P. E. Interlocked feedback loops within the Drosophila circadian oscillator. Science 286, 766–768 (1999).

    CAS  Google Scholar 

  41. 41

    Ralph, M. R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225–1227 (1988).

    ADS  CAS  Google Scholar 

  42. 42

    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  PubMed  PubMed Central  Google Scholar 

  43. 43

    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  Google Scholar 

  44. 44

    Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68 (1999).

    CAS  Google Scholar 

  45. 45

    Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Bae, K. et al. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525–536 (2001).

    MathSciNet  CAS  Google Scholar 

  47. 47

    Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001).

    CAS  Google Scholar 

  48. 48

    Gotter, A. L. et al. A time-less function for mouse Timeless. Nature Neurosci. 3, 755–756 (2000).

    CAS  Google Scholar 

  49. 49

    Lee, C., Parikh, V., Itsukaichi, T., Bae, K. & Edery, I. Resetting the Drosophila clock by photic regulation of PER and a PER-TIM complex. Science 271, 1740–1744 (1996).

    ADS  CAS  Google Scholar 

  50. 50

    Myers, M. P., Wager-Smith, K., Rothenfluh-Hilfiker, A. & Young, M. W. Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science 271, 1736–1740 (1996).

    ADS  CAS  Google Scholar 

  51. 51

    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  Google Scholar 

  52. 52

    Zimmerman, W. F. & Goldsmith, T. H. Photosensitivity of the circadian rhythm and of visual receptors in carotenoid-depleted Drosophila. Science 171, 1167–1169 (1971).

    ADS  CAS  Google Scholar 

  53. 53

    Wheeler, D. A., Hamblen-Coyle, M. J., Dushay, M. S. & Hall, J. C. Behavior in light-dark cycles of Drosophila mutants that are arrhythmic, blind, or both. J. Biol. Rhythms 8, 67–94 (1993).

    CAS  Google Scholar 

  54. 54

    Thompson, C. L. et al. Preservation of light signaling to the suprachiasmatic nucleus in vitamin A-deficient mice. Proc. Natl Acad. Sci. USA 98, 11708–11713 (2001).

    ADS  CAS  PubMed  Google Scholar 

  55. 55

    Czeisler, C. A. et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N. Engl. J. Med. 332, 6–11 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Stanewsky, R. et al. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 95, 681–692 (1998).

    CAS  Google Scholar 

  57. 57

    Emery, P., So, W. V., Kaneko, M., Hall, J. C. & Rosbash, M. CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity. Cell 95, 669–679 (1998).

    CAS  Google Scholar 

  58. 58

    Ceriani, M. F. et al. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553–556 (1999).

    CAS  Google Scholar 

  59. 59

    Naidoo, N., Song, W., Hunter-Ensor, M. & Sehgal, A. A role for the proteasome in the light response of the timeless clock protein. Science 285, 1737–1741 (1999).

    CAS  Google Scholar 

  60. 60

    Lin, F. J., Song, W., Meyer-Bernstein, E., Naidoo, N. & Sehgal, A. Photic signaling by cryptochrome in the Drosophila circadian system. Mol. Cell. Biol. 21, 7287–7294 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Krishnan, B. et al. A new role for cryptochrome in a Drosophila circadian oscillator. Nature 411, 313–317 (2001).

    ADS  CAS  Google Scholar 

  62. 62

    Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Lee, C., Etchegaray, J. P., Cagampang, F. R., Loudon, A. S. & Reppert, S. M. Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855–867 (2001).

    CAS  Google Scholar 

  64. 64

    van der Horst, G. T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).

    ADS  CAS  Google Scholar 

  65. 65

    Takahashi, J. S., DeCoursey, P. J., Bauman, L. & Menaker, M. Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 308, 186–188 (1984).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Lucas, R. J. et al. Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav. Brain Res. 125, 97–102 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Antoch, M. P. et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Newby, L. M. & Jackson, F. R. A new biological rhythm mutant of Drosophila melanogaster that identifies a gene with an essential embryonic function. Genetics 135, 1077–1090 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Renn, S. C., Park, J. H., Rosbash, M., Hall, J. C. & Taghert, P. H. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99, 791–802 (1999).

    CAS  Google Scholar 

  70. 70

    Sarov-Blat, L., So, W. V., Liu, L. & Rosbash, M. The Drosophila takeout gene is a novel molecular link between circadian rhythms and feeding behavior. Cell 101, 647–656 (2000).

    CAS  Google Scholar 

  71. 71

    Harmer, S. L. et al. Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290, 2110–2113 (2000).

    ADS  CAS  Google Scholar 

  72. 72

    Grundschober, C. et al. Circadian regulation of diverse gene products revealed by mRNA expression profiling of synchronized fibroblasts. J. Biol. Chem. 276, 46751–46758 (2001).

    CAS  Google Scholar 

  73. 73

    McDonald, M. J. & Rosbash, M. Microarray analysis and organization of circadian gene expression in Drosophila. Cell 107, 567–578 (2001).

    CAS  Google Scholar 

  74. 74

    Claridge-Chang, A. et al. Circadian regulation of gene expression systems in the Drosophila head. Neuron 32, 657–671 (2001).

    CAS  Google Scholar 

  75. 75

    Ceriani, M. F. et al. Genome-wide expression analysis in Drosophila predicts genes controlling circadian behavior. (Submitted.)

  76. 76

    Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell (in the press).

  77. 77

    Alabadi, D. et al. Reciprocal regulation between TOC1 and LHY/CCA1 within the Arabidopsis circadian clock. Science 293, 880–883 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Doi, M., Nakajima, Y., Okano, T. & Fukada, Y. Light-induced phase-delay of the chicken pineal circadian clock is associated with the induction of cE4bp4, a potential transcriptional repressor of cPer2 gene. Proc. Natl Acad. Sci. USA 98, 8089–8094 (2001).

    ADS  CAS  PubMed  Google Scholar 

  79. 79

    Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y. & Okamura, H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev. 15, 995–1006 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Kaneko, M. & Hall, J. C. Neuroanatomy of cells expressing clock genes in Drosophila: transgenic manipulation of the period and timeless genes to mark the perikarya of circadian pacemaker neurons and their projections. J. Comp. Neurol. 422, 66–94 (2000).

    CAS  Google Scholar 

  81. 81

    van Esseveldt, K. E., Lehman, M. N. & Boer, G. J. The suprachiasmatic nucleus and the circadian time-keeping system revisited. Brain Res. Brain Res. Rev. 33, 34–77 (2000).

    CAS  Google Scholar 

  82. 82

    Weiner, J. Time, Love, Memory (Vintage Books, New York, 1999).

    Google Scholar 

  83. 83

    Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Keesler, G. A. et al. Phosphorylation and destabilization of human period 1 clock protein by human casein kinase Iε. NeuroReport 11, 951–955 (2000).

    CAS  Google Scholar 

  85. 85

    Vielhaber, E., Eide, E., Rivers, A., Gao, Z. H. & Virshup, D. M. Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase Iε. Mol. Cell. Biol. 20, 4888–4899 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Steve A. Kay.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Panda, S., Hogenesch, J. & Kay, S. Circadian rhythms from flies to human. Nature 417, 329–335 (2002). https://doi.org/10.1038/417329a

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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