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.

  • Review Article
  • Published:

Mammalian circadian signaling networks and therapeutic targets

Nature Chemical Biology volume 3, pages 630–639 (2007)Cite this article

Abstract

Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is a key feature of the circadian clock system. In particular, intercellular coupling in the SCN synchronizes neuron oscillators and confers robustness against perturbations. Recent advances in our knowledge of and ability to manipulate circadian rhythms make available cell-based clock models, which lack strong coupling and are ideal for target discovery and chemical biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The mammalian circadian intracellular clockwork.
Figure 2: Graphical representation of circadian terms relating to cellular gene expression.
Figure 3: The mammalian circadian timekeeping system.
Figure 4: External synchronization of the SCN to light-dark cycles.
Figure 5: Intercellular synchronization among SCN neurons.
Figure 6: Internal synchronization at the organismal level.
Figure 7: Chemical probe discovery in circadian biology.

Similar content being viewed by others

References

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Ueda, H.R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Reppert, S.M. & Weaver, D.R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).

    CAS  PubMed  Google Scholar 

  6. Gallego, M. & Virshup, D.M. Post-translational modifications relgulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8, 139–148 (2007).

    CAS  PubMed  Google Scholar 

  7. Yoo, S.H. et al. PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl. Acad. Sci. USA 101, 5339–5346 (2004).

    CAS  PubMed  Google Scholar 

  8. Welsh, D.K., Yoo, S.H., Liu, 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  PubMed  PubMed Central  Google Scholar 

  9. Liu, A.C. et al. Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129, 605–616 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nagoshi, E. et al. Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells. Cell 119, 693–705 (2004).

    CAS  PubMed  Google Scholar 

  11. van den Pol, A.N. & Dudek, F.E. Cellular communication in the circadian clock, the suprachiasmatic nucleus. Neuroscience 56, 793–811 (1993).

    CAS  PubMed  Google Scholar 

  12. Low-Zeddies, S.S. & Takahashi, J.S. Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior. Cell 105, 25–42 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  PubMed  Google Scholar 

  14. Aton, S.J. & Herzog, E.D. Come together, right...now: synchronization of rhythms in a mammalian circadian clock. Neuron 48, 531–534 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakamura, W., Honma, S., Shirakawa, T. & Honma, K. Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nat. Neurosci. 5, 399–400 (2002).

    CAS  PubMed  Google Scholar 

  16. Herzog, E.D., Aton, S.J., Numano, R., Sakaki, Y. & Tei, H. Temporal precision in the mammalian circadian system: a reliable clock from less reliable neurons. J. Biol. Rhythms 19, 35–46 (2004).

    PubMed  Google Scholar 

  17. Horikawa, K., Ishimatsu, K., Yoshimoto, E., Kondo, S. & Takeda, H. Noise-resistant and synchronized oscillation of the segmentation clock. Nature 441, 719–723 (2006).

    CAS  PubMed  Google Scholar 

  18. Masamizu, Y. et al. Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc. Natl. Acad. Sci. USA 103, 1313–1318 (2006).

    CAS  PubMed  Google Scholar 

  19. Foster, R.G. et al. Circadian photoreception in the retinally degenerate mouse (rd/rd). J. Comp. Physiol. [A] 169, 39–50 (1991).

    CAS  Google Scholar 

  20. Panda, S. et al. Illumination of the melanopsin signaling pathway. Science 307, 600–604 (2005).

    CAS  PubMed  Google Scholar 

  21. Melyan, Z., Tarttelin, E.E., Bellingham, J., Lucas, R.J. & Hankins, M.W. Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433, 741–745 (2005).

    CAS  PubMed  Google Scholar 

  22. Qiu, X. et al. Induction of photosensitivity by heterologous expression of melanopsin. Nature 433, 745–749 (2005).

    CAS  PubMed  Google Scholar 

  23. Dacey, D.M. et al. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN. Nature 433, 749–754 (2005).

    CAS  PubMed  Google Scholar 

  24. 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  PubMed  PubMed Central  Google Scholar 

  25. Berson, D.M., Dunn, F.A. & Takao, M. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295, 1070–1073 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Panda, S. et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213–2216 (2002).

    CAS  PubMed  Google Scholar 

  28. Ruby, N.F. et al. Role of melanopsin in circadian responses to light. Science 298, 2211–2213 (2002).

    CAS  PubMed  Google Scholar 

  29. Lucas, R.J. et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299, 245–247 (2003).

    CAS  PubMed  Google Scholar 

  30. Hattar, S. et al. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424, 76–81 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Panda, S. et al. Melanopsin is required for non-image-forming photic responses in blind mice. Science 301, 525–527 (2003).

    CAS  PubMed  Google Scholar 

  32. Meijer, J.H. & Schwartz, W.J. In search of the pathways for light-induced pacemaker resetting in the suprachiasmatic nucleus. J. Biol. Rhythms 18, 235–249 (2003).

    PubMed  Google Scholar 

  33. Antle, M.C. & Silver, R. Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci. 28, 145–151 (2005).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  36. Travnickova-Bendova, Z., Cermakian, N., Reppert, S.M. & Sassone-Corsi, P. Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc. Natl. Acad. Sci. USA 99, 7728–7733 (2002).

    CAS  PubMed  Google Scholar 

  37. Tischkau, S.A., Mitchell, J.W., Tyan, S.H., Buchanan, G.F. & Gillette, M.U. Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J. Biol. Chem. 278, 718–723 (2003).

    CAS  PubMed  Google Scholar 

  38. Gillette, M.U. & Mitchell, J.W. Signaling in the suprachiasmatic nucleus: selectively responsive and integrative. Cell Tissue Res. 309, 99–107 (2002).

    CAS  PubMed  Google Scholar 

  39. Tischkau, S.A. et al. Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock. Neuron 43, 539–549 (2004).

    CAS  PubMed  Google Scholar 

  40. Yamaguchi, S. et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science 302, 1408–1412 (2003).

    CAS  PubMed  Google Scholar 

  41. Albus, H. et al. Cryptochrome-deficient mice lack circadian electrical activity in the suprachiasmatic nuclei. Curr. Biol. 12, 1130–1133 (2002).

    CAS  PubMed  Google Scholar 

  42. 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).

    CAS  PubMed  Google Scholar 

  43. Herzog, E.D., Takahashi, J.S. & Block, G.D. Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat. Neurosci. 1, 708–713 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  45. Albus, H., Vansteensel, M.J., Michel, S., Block, G.D. & Meijer, J.H.A. GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock. Curr. Biol. 15, 886–893 (2005).

    CAS  PubMed  Google Scholar 

  46. Harmar, A.J. et al. The VPAC(2) receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109, 497–508 (2002).

    CAS  Google Scholar 

  47. Colwell, C.S. et al. Disrupted circadian rhythms in VIP- and PHI-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R939–R949 (2003).

    CAS  PubMed  Google Scholar 

  48. Aton, S.J., Colwell, C.S., Harmar, A.J., Waschek, J. & Herzog, E.D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Maywood, E.S. et al. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr. Biol. 16, 599–605 (2006).

    CAS  PubMed  Google Scholar 

  50. Cutler, D.J. et al. The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro. Eur. J. Neurosci. 17, 197–204 (2003).

    PubMed  Google Scholar 

  51. Aida, R. et al. Gastrin-releasing peptide mediates photic entrainable signals to dorsal subsets of suprachiasmatic nucleus via induction of Period gene in mice. Mol. Pharmacol. 61, 26–34 (2002).

    CAS  PubMed  Google Scholar 

  52. Piggins, H.D., Antle, M.C. & Rusak, B. Neuropeptides phase shift the mammalian circadian pacemaker. J. Neurosci. 15, 5612–5622 (1995).

    CAS  PubMed  Google Scholar 

  53. McArthur, A.J. et al. Gastrin-releasing peptide phase-shifts suprachiasmatic nuclei neuronal rhythms in vitro. J. Neurosci. 20, 5496–5502 (2000).

    CAS  PubMed  Google Scholar 

  54. Brown, T.M., Hughes, A.T. & Piggins, H.D. Gastrin-releasing peptide promotes suprachiasmatic nuclei cellular rhythmicity in the absence of vasoactive intestinal polypeptide-VPAC2 receptor signaling. J. Neurosci. 25, 11155–11164 (2005).

    CAS  PubMed  Google Scholar 

  55. Long, M.A., Jutras, M.J., Connors, B.W. & Burwell, R.D. Electrical synapses coordinate activity in the suprachiasmatic nucleus. Nat. Neurosci. 8, 61–66 (2005).

    CAS  PubMed  Google Scholar 

  56. Nitabach, M.N., Blau, J. & Holmes, T.C. Electrical silencing of Drosophila pacemaker neurons stops the free-running circadian clock. Cell 109, 485–495 (2002).

    CAS  PubMed  Google Scholar 

  57. Aton, S.J., Huettner, J.E., Straume, M. & Herzog, E.D. GABA and Gi/o differentially control circadian rhythms and synchrony in clock neurons. Proc. Natl. Acad. Sci. USA 103, 19188–19193 (2006).

    CAS  PubMed  Google Scholar 

  58. Kuhlman, S.J. & McMahon, D.G. Encoding the ins and outs of circadian pacemaking. J. Biol. Rhythms 21, 470–481 (2006).

    CAS  PubMed  Google Scholar 

  59. Buijs, R.M. & Kalsbeek, A. Hypothalamic integration of central and peripheral clocks. Nat. Rev. Neurosci. 2, 521–526 (2001).

    CAS  PubMed  Google Scholar 

  60. Kalsbeek, A. et al. SCN outputs and the hypothalamic balance of life. J. Biol. Rhythms 21, 458–469 (2006).

    CAS  PubMed  Google Scholar 

  61. Schibler, U., Ripperger, J. & Brown, S.A. Peripheral circadian oscillators in mammals: time and food. J. Biol. Rhythms 18, 250–260 (2003).

    PubMed  Google Scholar 

  62. Silver, R., LeSauter, J., Tresco, P.A. & Lehman, M.N. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382, 810–813 (1996).

    CAS  PubMed  Google Scholar 

  63. Pando, M.P., Morse, D., Cermakian, N. & Sassone-Corsi, P. Phenotypic rescue of a peripheral clock genetic defect via SCN hierarchical dominance. Cell 110, 107–117 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  65. Abrahamson, E.E., Leak, R.K. & Moore, R.Y. The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12, 435–440 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Tousson, E. & Meissl, H. Suprachiasmatic nuclei grafts restore the circadian rhythm in the paraventricular nucleus of the hypothalamus. J. Neurosci. 24, 2983–2988 (2004).

    CAS  PubMed  Google Scholar 

  68. Kramer, A. et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 294, 2511–2515 (2001).

    CAS  PubMed  Google Scholar 

  69. Cheng, M.Y. et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410 (2002).

    CAS  PubMed  Google Scholar 

  70. Kraves, S. & Weitz, C.J. A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat. Neurosci. 9, 212–219 (2006).

    CAS  PubMed  Google Scholar 

  71. Prosser, H.M. et al. Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc. Natl. Acad. Sci. USA 104, 648–653 (2007).

    CAS  PubMed  Google Scholar 

  72. Li, J.D. et al. Attenuated circadian rhythms in mice lacking the prokineticin 2 gene. J. Neurosci. 26, 11615–11623 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Balsalobre, A. et al. Resetting of circadian time peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

    CAS  PubMed  Google Scholar 

  74. Jusko, W.J. Pharmacokinetics and receptor-mediated pharmacodynamics of corticosteroids. Toxicology 102, 189–196 (1995).

    CAS  PubMed  Google Scholar 

  75. Hastings, M.H., Reddy, A.B. & Maywood, E.S. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat. Rev. Neurosci. 4, 649–661 (2003).

    CAS  PubMed  Google Scholar 

  76. Labrecque, G., Bureau, J.P. & Reinberg, A.E. Biological rhythms in the inflammatory response and in the effects of nonsteroidal antiinflammatory drugs. Pharmacol. Ther. 66, 285–300 (1995).

    CAS  PubMed  Google Scholar 

  77. Mormont, M.C. & Levi, F. Cancer chronotherapy: principles, applications, and perspectives. Cancer 97, 155–169 (2003).

    CAS  PubMed  Google Scholar 

  78. Levi, F. & Schibler, U. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593–628 (2007).

    CAS  PubMed  Google Scholar 

  79. Pace-Schott, E.F. & Hobson, J.A. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat. Rev. Neurosci. 3, 591–605 (2002).

    CAS  PubMed  Google Scholar 

  80. Dijk, D. & von Schantz, M. Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators. J. Biol. Rhythms 20, 279–290 (2005).

    PubMed  Google Scholar 

  81. Morin, A.K., Jarvis, C.I. & Lynch, A.M. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 27, 89–110 (2007).

    CAS  PubMed  Google Scholar 

  82. Atack, J.R. The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. Expert Opin. Investig. Drugs 14, 601–618 (2005).

    CAS  Google Scholar 

  83. Borjigin, J., Li, X.D. & Snyder, S.H. The pineal gland and melatonin: molecular and pharmacologic regulation. Annu. Rev. Pharmacol. Toxicol. 39, 53–65 (1999).

    CAS  PubMed  Google Scholar 

  84. Kato, K. et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology 48, 301–310 (2005).

    CAS  PubMed  Google Scholar 

  85. Carrillo-Vico, A., Guerrero, J.M., Lardone, P.J. & Reiter, R.J. A review of the multiple actions of melatonin on the immune system. Endocrine 27, 189–200 (2005).

    CAS  PubMed  Google Scholar 

  86. McClung, C.A. Circadian genes, rhythms and the biology of mood disorders. Pharmacol. Ther. 114, 222–232 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yin, L., Wang, J., Klein, P.S. & Lazar, M.A. Nuclear receptor Rev-erba is a critical lithium-sensitive component of the circadian clock. Science 311, 1002–1005 (2006).

    CAS  PubMed  Google Scholar 

  88. Preitner, N. et al. The orphan nuclear receptor REV-ERB alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    CAS  PubMed  Google Scholar 

  89. Iitaka, C., Miyazaki, K., Akaike, T. & Ishida, N. A role for glycogen synthase kinase-3 beta in the mammalian circadian clock. J. Biol. Chem. 280, 29397–29402 (2005).

    CAS  PubMed  Google Scholar 

  90. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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  PubMed  Google Scholar 

  92. Vitaterna, M.H. et al. The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude. Proc. Natl. Acad. Sci. USA 103, 9327–9332 (2006).

    CAS  PubMed  Google Scholar 

  93. Brisbare-Roch, C. et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat. Med. 13, 150–155 (2007).

    CAS  PubMed  Google Scholar 

  94. Takahashi, J.S. Finding new clock components: past and future. J. Biol. Rhythms 19, 339–347 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Brown, S.A. et al. The period length of fibroblast circadian gene expression varies widely among human individuals. PLoS Biol. 3, e338 (2005).

    PubMed  PubMed Central  Google Scholar 

  96. Missbach, M. et al. Thiazolidine diones, specific ligands of the nuclear receptor retinoid Z receptor/retinoid acid receptor-related orphan receptor alpha with potent antiarthritic activity. J. Biol. Chem. 271, 13515–13522 (1996).

    CAS  PubMed  Google Scholar 

  97. Littman, D.R. et al. The role of the nuclear hormone receptor ROR gamma in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195, 81–90 (2003).

    PubMed  Google Scholar 

  98. Boukhtouche, F., Mariani, J. & Tedgui, A. The “CholesteROR” protective pathway in the vascular system. Arterioscler. Thromb. Vasc. Biol. 24, 637–643 (2004).

    CAS  PubMed  Google Scholar 

  99. Eide, E.J. et al. Control of mammalian circadian rhythm by CKI epsilon-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795–2807 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Siepka, S.M. et al. The circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryprochrome and period gene expression. Cell 129, 1011–1023 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Busino, L. et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316, 900–904 (2007).

    CAS  PubMed  Google Scholar 

  102. Godinho, S.I.H. et al. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316, 897–900 (2007).

    CAS  PubMed  Google Scholar 

  103. Kornmann, B., Schaad, O., Bujard, H., Takahashi, J.S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007).

    PubMed  PubMed Central  Google Scholar 

  104. Brown, S.A., Zumbrunn, G., Fleury-Olela, F., Preitner, N. & Schibler, U. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr. Biol. 12, 1574–1583 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D.K. Welsh for helpful discussion and critical reading of the manuscript. This work was supported in part by grants from the US National Institutes of Health (R01 GM074868 and R01 MH051573 to S.A.K.).

Author information

Author notes

  1. Andrew C Liu, Warren G Lewis & Steve A Kay

    Present address: Present address: Cell and Developmental Biology, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0130, USA.,

Authors and Affiliations

  1. Department of Biochemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Andrew C Liu, Warren G Lewis & Steve A Kay

  2. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, 92121, California, USA

    Andrew C Liu & Warren G Lewis

Authors
  1. Andrew C Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Warren G Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Steve A Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steve A Kay.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, A., Lewis, W. & Kay, S. Mammalian circadian signaling networks and therapeutic targets. Nat Chem Biol 3, 630–639 (2007). https://doi.org/10.1038/nchembio.2007.37

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.2007.37

This article is cited by

Search

Advanced 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