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  • Review Article
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Multilevel regulation of the circadian clock

Nature Reviews Molecular Cell Biology volume 1, pages 59–67 (2000)Cite this article

Abstract

Living organisms adapt to light–dark rhythmicity using a complex programme based on internal clocks. These circadian clocks, which are regulated by the environment, direct various physiological functions. As the molecular mechanisms that govern clock function are unravelled, we are starting to appreciate simple patterns as well as exquisite layers of regulation.

Key Points

  • Living organisms adapt to light–dark rhythmicity using a complex programme based on internal clocks.

  • In mammals, the central clock structure is located within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.

  • The clock can be considered as consisting of three overlapping components: the input pathways, the oscillator or pacemaker (which generates rhythmicity autonomously) and the output pathways.

  • Input-gene products are thought to sense external stimuli and relay the message to the oscillator to reset or entrain it.

  • Many pacemaker genes encode transcription factors or proteins that act on gene regulation, emphasizing the idea that the generation and modulation of rhythms relies mainly on transcriptional feedback loops and on activation and repression of gene expression (perhaps through chromatin remodelling).

  • The circadian clock probably uses a number of inter- or intragenic loops organized in networks.

  • Degradation of clock messenger RNAs and proteins is crucial to the control of oscillator periodicity. Entry of clock proteins into the nucleus is another checkpoint for circadian feedback loops.

  • Peripheral clocks may be controlled or synchronized by the SCN through blood-borne signalling factors oscillating in a circadian fashion.

  • Output gene-products, which include peptides and transcription factors, convey rhythmic information to downstream physiological systems.

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Figure 1: Anatomical location of the suprachiasmatic nuclei.
Figure 2: The circadian clock.
Figure 3: Model of the molecular mechanisms involved in the Drosophila circadian clock.
Figure 4: Model of the molecular mechanisms involved in the mammalian circadian clock.
Figure 5: Signalling within a suprachiasmatic nucleus synapse and neuron.

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References

  1. Menaker, M., Moreira, L. F. & Tosini, G. Evolution of circadian organization in vertebrates. Braz. J. Med. Biol. Res. 30, 305–313 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Pittendrigh, C. S. Temporal organization: reflections of a Darwinian clock-watcher. Annu. Rev. Physiol. 55, 16–54 (1993).An autobiographical essay by one of the fathers of modern chronobiology, covering the discovery of the basic principles of the discipline over fifty years.

    Article  CAS  PubMed  Google Scholar 

  3. Hastings, M. H. Central clocking. Trends Neurosci. 20, 459 –464 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Moore, R. Y. & Silver, R. Suprachiasmatic nucleus organization . Chronobiol. Int. 15, 475– 487 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999).A comprehensive review on the genetics of the circadian clocks in cyanobacteria, fungi, Drosophila , mammals and plants.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. King, D. P. et al. Positional cloning of the mouse circadian Clock gene . Cell 89, 641–653 (1997).The conclusion of an impressive study that led to the identification of the first mammalian clock gene, named Clock.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism . Science 280, 1564–1569 (1998).A key paper about a basic device, the feedback loop: the positive elements of the loop were finally uncovered.

    Article  CAS  PubMed  Google Scholar 

  11. 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).Circadian photoreception in Drosophila is the duty of cryptochrome, a homologue of light-receiving proteins in plants.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Foster, R. G. & Lucas, R. J. Clocks, criteria and critical genes . Nature Genet. 22, 217– 219 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, C., Bae, K. & Edery, I. PER and TIM inhibit the DNA binding activity of a Drosophila CLOCK-CYC/dBMAL1 heterodimer without disrupting formation of the heterodimer: a basis for circadian transcription. Mol. Cell. Biol. 19, 5316 –5325 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57– 68 (1999).This was the first paper establishing a molecular link between the central clockworks and the expression of an output gene.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Griffin, E. A. Jr, Staknis, D. & Weitz, C. J. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286, 768–771 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock . Science 288, 1013–1019 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Yagita, K. et al. Dimerization and nuclear entry of mPER proteins in mammalian cells. Genes Dev. 14, 1353– 1363 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Cermakian, N., Whitmore, D., Foulkes, N. S. & Sassone-Corsi, P. Asynchronous oscillations of two zebrafish CLOCK partners reveal differential clock control and function. Proc. Natl Acad. Sci. USA 97, 4339–4344 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hogenesch, J. B. et al. The basic helix-loop-helix-PAS protein MOP9 is a brain-specific heterodimeric partner of circadian and hypoxia factors. J. Neurosci. 20, 1–5 (2000 ).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oishi, K., Sakamoto, K., Okada, T., Nagase, T. & Ishida, N. Antiphase circadian expression between BMAL1 and period homologue mRNA in the suprachiasmatic nucleus and peripheral tissues of rats. Biochem. Biophys. Res. Commun. 253 , 199–203 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Bae, K., Lee, C., Hardin, P. E. & Edery, I. dCLOCK is present in limiting amounts and likely mediates daily interactions between the dCLOCK-CYC transcription factor and the PER-TIM complex. J. Neurosci. 20, 1746–1753 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Lee, K., Loros, J. J. & Dunlap, J. C. Interconnected feedback loops in the Neurospora circadian system. Science 289, 107– 110 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Lucas, R. J. & Foster, R. G. Circadian clocks: A cry in the dark? Curr. Biol. 9, 825– 828 (1999).

    Article  Google Scholar 

  33. Park, J. H. et al. Differential regulation of circadian pacemaker output by separate clock genes in Drosophila. Proc. Natl Acad. Sci. USA 97, 3608–3613 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Gotter, A. L., Levine, J. D. & Reppert, S. M. Sex-linked period genes in the silkmoth, Antheraea pernyi: implications for circadian clock regulation and the evolution of sex chromosomes. Neuron 24, 953– 965 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Ding, J. M. et al. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science 266, 1713–1717 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Kornhauser, J. M., Nelson, D. E., Mayo, K. E. & Takahashi, J. S. Photic and circadian regulation of c-fos gene expression in the hamster suprachiasmatic nucleus. Neuron 5, 127– 134 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Morris, M. E., Viswanathan, N., Kuhlman, S., Davis, F. C. & Weitz, C. J. A screen for genes induced in the suprachiasmatic nucleus by light. Science 279, 1544–1547 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Shearman, L. P., Zylka, M. J., Weaver, D. R., Kolakowski, L. F. Jr & Reppert, S. M. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19, 1261– 1269 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Akiyama, M. et al. Inhibition of light- or glutamate-induced mPer1 expression represses the phase shifts into the mouse circadian locomotor and suprachiasmatic firing rhythms. J. Neurosci. 19, 1115– 1121 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Wollnik, F. et al. Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock. Eur. J. Neurosci. 7, 388–393 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Ginty, D. D. et al. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260 , 238–241 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Obrietan, K., Impey, S., Smith, D., Athos, J. & Storm, D. R. Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J. Biol. Chem. 274, 17748–17756 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Belvin, M. P., Zhou, H. & Yin, J. C. The Drosophila dCREB2 gene affects the circadian clock. Neuron 22, 777–787 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. de Cesare, D., Fimia, G. M. & Sassone-Corsi, P. Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends Biochem. Sci. 24, 281 –285 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Obrietan, K., Impey, S. & Storm, D. R. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature Neurosci. 1, 693–700 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Akashi, M. & Nishida, E. Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev. 14, 645–649 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ding, J. M. et al. A neuronal ryanodine receptor mediates light-induced phase delays of the circadian clock. Nature 394, 381–384 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Hastings, M. H. et al. Non-photic signalling in the suprachiasmatic nucleus. Biol. Cell 89, 495–503 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  50. Maywood, E. S., Mrosovsky, N., Field, M. D. & Hastings, M. H. Rapid down-regulation of mammalian period genes during behavioral resetting of the circadian clock. Proc. Natl Acad. Sci. USA 96 , 15211–15216 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Shinohara, K., Hiruma, H., Funabashi, T. & Kimura, F. GABAergic modulation of gap junction communication in slice cultures of the rat suprachiasmatic nucleus. Neuroscience 96, 591–596 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Pickard, G. E. & Rea, M. A. Serotonergic innervation of the hypothalamic suprachiasmatic nucleus and photic regulation of circadian rhythms. Biol. Cell 89, 513– 523 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Liu, C. et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19, 91–102 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Liu, C. & Reppert, S. M. GABA synchronizes clock cells within the suprachiasmatic circadian clock. Neuron 25, 123–128 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Cheung, P., Allis, C. D. & Sassone–Corsi, P. Signaling to chromatin through histone modifications. Cell (in the press).

  57. Workman, J. L. & Kingston, R. E. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu. Rev. Biochem. 67, 545–579 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Ko, H. P., Okino, S. T., Ma, Q. & Whitlock, J. P. Jr Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure. Mol. Cell. Biol. 16, 430–436 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kobayashi, A., Numayama-Tsuruta, K., Sogawa, K. & Fujii-Kuriyama, Y. CBP/p300 functions as a possible transcriptional coactivator of Ah receptor nuclear translocator (Arnt). J. Biochem. 122, 703–710 (1997).

    Article  CAS  PubMed  Google Scholar 

  60. Yao, T. P., Ku, G., Zhou, N., Scully, R. & Livingston, D. M. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc. Natl Acad. Sci. USA 93, 10626–10631 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. de Cesare, D., Jacquot, S., Hanauer, A. & Sassone-Corsi, P. Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. Proc. Natl Acad. Sci. USA 95, 12202–12207 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  62. Sassone-Corsi, P. et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285, 886–891 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Dembinska, M. E., Stanewsky, R., Hall, J. C. & Rosbash, M. Circadian cycling of a PERIOD-beta-galactosidase fusion protein in Drosophila : evidence for cyclical degradation. J. Biol. Rhythms 12, 157–172 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. So, W. V. & Rosbash, M. Post-transcriptional regulation contributes to Drosophila clock gene mRNA cycling. EMBO J. 16, 7146–7155 ( 1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ruoff, P., Vinsjevik, M., Monnerjahn, C. & Rensing, L. The Goodwin oscillator: on the importance of degradation reactions in the circadian clock. J. Biol. Rhythms 14, 469 –479 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94 , 83–95 (1998). This was the first paper to identify a regulatory protein involved in the modification of other clock proteins.

    Article  CAS  PubMed  Google Scholar 

  67. Liu, Y., Loros, J. & Dunlap, J. C. Phosphorylation of the Neurospora clock protein FREQUENCY determines its degradation rate and strongly influences the period length of the circadian clock. Proc. Natl Acad. Sci. USA 97, 234–239 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Talora, C., Franchi, L., Linden, H., Ballario, P. & Macino, G. Role of a white collar-1-white collar-2 complex in blue-light signal transduction. EMBO J. 18, 4961– 4968 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nelson, D. C., Lasswell, J., Rogg, L. E., Cohen, M. A. & Bartel, B. FKF1, a clock-controlled gene that regulates the transition to flowering in Arabidopsis. Cell 101, 331–340 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  70. Somers, D. E., Schultz, T. F., Milnamow, M. & Kay, S. A. ZEITLUPE encodes a novel clock-associated PAS protein from Arabidopsis . Cell 101, 319–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. 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 I epsilon. Mol. Cell. Biol. 20, 4888–4899 ( 2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Okamura, H. et al. Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286, 2531–2534 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Vitaterna, M. H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Foster, R. G. Shedding light on the biological clock. Neuron 20, 829–832 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Freedman, M. S. et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284, 502– 504 (1999).Along with reference 76, this represented a big leap forward in the search for the mammalian circadian photoreceptor: it is neither the cones nor the rods, and so lies elsewhere in the retina.

    Article  CAS  PubMed  Google Scholar 

  76. Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J. M. & Foster, R. G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  77. Provencio, I. & Foster, R. G. Circadian rhythms in mice can be regulated by photoreceptors with cone-like characteristics. Brain Res. 694, 183–190 (1995).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Kojima, D., Mano, H. & Fukada, Y. Vertebrate ancient-long opsin: a green-sensitive photoreceptive molecule present in zebrafish deep brain and retinal horizontal cells. J. Neurosci. 20, 2845–2851 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Soni, B. G., Philp, A. R., Foster, R. G. & Knox, B. E. Novel retinal photoreceptors. Nature 394, 27–28 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Provencio, I. et al. A novel human opsin in the inner retina. J. Neurosci. 20, 600–605 ( 2000).

    Article  CAS  PubMed  Google Scholar 

  82. David-Gray, Z. K., Janssen, J. W., DeGrip, W. J., Nevo, E. & Foster, R. G. Light detection in a ‘blind’ mammal. Nature Neurosci. 1, 655– 656 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Whitmore, D., Foulkes, N. S. & Sassone-Corsi, P. Light acts directly on organs and cells in culture to set the vertebrate circadian clock. Nature 404, 87–91 (2000).The striking message of this paper is that the peripheral organs and cells of zebrafish not only behave as independent clocks, but they have all the machinery to receive light and interpret these signals.

    Article  CAS  PubMed  Google Scholar 

  84. Wade, P. D., Taylor, J. & Siekevitz, P. Mammalian cerebral cortical tissue responds to low-intensity visible light. Proc. Natl Acad. Sci. USA 85, 9322–9366 (1988).

    Article  CAS  PubMed  Google Scholar 

  85. LeSauter, J. & Silver, R. Output signals of the SCN. Chronobiol. Int. 15, 535–550 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Ueyama, T. et al. Suprachiasmatic nucleus: a central autonomic clock. Nature Neurosci. 2, 1051–1053 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929– 937 (1998).This paper reports the first case of circadian oscillations in non-neuronal mammalian cells in culture.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. Ripperger, J. A., Shearman, L. P., Reppert, S. M. & Schibler, U. CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes Dev. 14, 679–689 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. Mueller, C. R., Maire, P. & Schibler, U. DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally . Cell 61, 279–291 (1990).

    Article  CAS  PubMed  Google Scholar 

  93. Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M. & Schibler, U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. EMBO J. 16, 6762–6771 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Yamaguchi, S. et al. Role of DBP in the circadian oscillatory mechanism. Mol. Cell. Biol. 20, 4773–4781 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Foulkes, N. S., Borjigin, J., Snyder, S. H. & Sassone-Corsi, P. Rhythmic transcription: the molecular basis of circadian melatonin synthesis . Trends Neurosci. 20, 487– 492 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Andretic, R., Chaney, S. & Hirsh, J. Requirement of circadian genes for cocaine sensitization in Drosophila. Science 285, 1066– 1068 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Kuhlman, S. J., Quintero, J. E. & McMahon, D. G. GFP fluorescence reports Period 1 circadian gene regulation in the mammalian biological clock. Neuroreport 11, 1479–1482 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Liu, C., Weaver, D. R., Strogatz, S. H. & Reppert, S. M. Cellular construction of a circadian clock: period determination in the suprachiasmatic nuclei. Cell 91, 855–860 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Tosini, G. & Menaker, M. Circadian rhythms in cultured mammalian retina. Science 272, 419– 421 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Plautz, J. D., Kaneko, M., Hall, J. C. & Kay, S. A. Independent photoreceptive circadian clocks throughout Drosophila. Science 278, 1632–1635 (1997). This paper presents the first description of independent non-neural peripheral clocks in animals.

    Article  CAS  PubMed  Google Scholar 

  101. Giebultowicz, J. M., Stanewsky, R., Hall, J. C. & Hege, D. M. Transplanted Drosophila excretory tubules maintain circadian clock cycling out of phase with the host. Curr. Biol. 10, 107–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Whitmore, D., Foulkes, N. S., Strahle, U. & Sassone-Corsi, P. Zebrafish Clock rhythmic expression reveals independent peripheral circadian oscillators. Nature Neurosci. 1, 701–707 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  104. Krishnan, B., Dryer, S. E. & Hardin, P. E. Circadian rhythms in olfactory responses of Drosophila melanogaster. Nature 400, 375– 378 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Sakamoto, K. et al. Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J. Biol. Chem. 273, 27039–27042 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to apologize to all colleagues whose work, because of lack of space, could not be cited. We thank all the members of the Sassone-Corsi laboratory for helpful discussions. N.C. was supported by a Human Frontier Science Program Organization long-term fellowship and a Canadian Institutes of Health Research postdoctoral fellowship. Work in our laboratory is supported by grants from CNRS, INSERM, CHUR, Human Frontier Science Program, Organon Akzo/Nobel, Fondation pour la Recherche Médicale and Association pour la Recherche sur le Cancer.

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  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS–INSERM–Université Louis Pasteur, 1, Rue Laurent Fries, Illkirch–Strasbourg, 67404, France

    Nicolas Cermakian & Paolo Sassone-Corsi

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  1. Nicolas Cermakian
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Correspondence to Paolo Sassone-Corsi.

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Per

tim

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cycle

dbt

Bmal1

PAS domain

AHR

SIM

CRY

bHLH domain

CRY1

CRY2

MOP9

pdf

c-fos

fos-B

NFGI-A

CREB

PKA

CBP

bHLH–PAS domain

PKG

ARNT

p300

SRC-1

Rsk-2

H3

CKIɛ

vrille

avp

dbp

CREM

ENCYCLOPEDIA OF LIFE SCIENCES

Circadian rhythms

Glossary

E-BOX ELEMENT

Promoter element recognized by transcription factors of the basic helix–loop–helix class.

PHASE SHIFT

A shift in the endogenous circadian rhythms that occurs when an organism is placed in different lighting regimes (or other external stimuli).

SUBJECTIVE NIGHT AND DAY

Correspond to the endogenous night–day circadian cycle of an organism, independent of the astronomical day and night.

HISTONE ACETYL-TRANSFERASES AND DEACETYLASES

Enzymes that modify histones by adding and removing acetyl groups, a chemical modification thought to remodel chromatin structure.

UBIQUITIN LIGASE

An enzyme that couples the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome.

PHOTOLYASE

A DNA repair enzyme that splits pyrimidine dimers (lesions caused by UV irradiation) into monomers.

OPSINS

Hydrophobic glycoproteins found in the visual pigments of vertebrates.

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Cermakian, N., Sassone-Corsi, P. Multilevel regulation of the circadian clock. Nat Rev Mol Cell Biol 1, 59–67 (2000). https://doi.org/10.1038/35036078

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