Skip to main content
SpringerLink
Log in

Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system

  • Review Article
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

A functional mouse CLOCK protein has long been thought to be essential for mammalian circadian clockwork function, based mainly on studies of mice bearing a dominant negative, antimorphic mutation in the Clock gene. However, new discoveries using recently developed Clock-null mutant mice have shaken up this view. In this review, I discuss how this recent work impacts and alters the previous view of the role of CLOCK in the mouse circadian clockwork.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Akashi M. and Takumi T. 2005 The orphan nuclear receptor RO-Ralpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat. Struct. Mol. Biol. 12, 441–448.

    Article  PubMed  CAS  Google Scholar 

  • Antoch M. P., Song E. J., Chang A. M., Vitaterna M. H., Zhao Y., Wilsbacher L. D. et al. 1997 Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89, 655–667.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bunger M. K., Wilsbacher L. D., Moran S. M., Clendenin C., Radcliffe L. A., Hogenesch J. B. et al. 2000 Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017.

    Article  PubMed  CAS  Google Scholar 

  • Cheng M. Y., Bullock C. M., Li C., Lee A. G., Bermak J. C., Belluzzi J. et al. 2002 Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417, 405–410.

    Article  PubMed  CAS  Google Scholar 

  • Cuninkova L. and Brown S. A. 2008 Peripheral circadian oscillators: interesting mechanisms and powerful tools. Ann. N. Y. Acad. Sci. 1129, 358–370.

    Article  PubMed  Google Scholar 

  • DeBruyne J. P., Noton E., Lambert C. M., Maywood E. S., Weaver D. R. and Reppert S. M. 2006 A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50, 465–477.

    Article  PubMed  CAS  Google Scholar 

  • DeBruyne J. P., Weaver D. R. and Reppert S. M. 2007a CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat. Neurosci. 10, 543–545.

    Article  PubMed  CAS  Google Scholar 

  • DeBruyne J. P., Weaver D. R. and Reppert S. M. 2007b Peripheral circadian oscillators require CLOCK. Curr. Biol. 17, 538–539.

    Article  CAS  Google Scholar 

  • Dudley C. A., Erbel-Sieler C., Estill S. J., Reick M., Franken P., Pitts S. and McKnight S. L. 2003 Altered patterns of sleep and behavioural adaptability in NPAS2-deficient mice. Science 301, 379–383.

    Article  PubMed  CAS  Google Scholar 

  • Duffield G. E. 2003 DNA microarray analyses of circadian timing: the genomic basis of biological time. J. Neuroendocrinol. 15, 991–1002.

    Article  PubMed  CAS  Google Scholar 

  • Emery P. and Reppert S. M. 2004 A rhythmic Ror. Neuron 43, 443–446.

    Article  PubMed  CAS  Google Scholar 

  • Etchegaray J. P., Lee C., Wade P. A. and Reppert S. M. 2003 Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182.

    Article  PubMed  CAS  Google Scholar 

  • Garcia J. A., Zhang D., Estill S. J., Michnoff C., Rutter J., Reick M. et al. 2000 Impaired cued and contextual memory in NPAS2-deficient mice. Science 288, 2226–2230.

    Article  PubMed  CAS  Google Scholar 

  • Gekakis N., Staknis D., Nguyen H. B., Davis F. C., Wilsbacher L. D., King D. P. et al. 1998 Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569.

    Article  PubMed  CAS  Google Scholar 

  • Green C. B. and Menaker M. 2003 Circadian rhythms: clocks on the brain. Science 301, 319–320.

    Article  PubMed  CAS  Google Scholar 

  • Hogenesch J. B., Chan W. K., Jackiw V. H., Brown R. C., Gu Y. Z., Pray-Grant M. et al. 1997 Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J. Biol. Chem. 272, 8581–8593.

    Article  PubMed  CAS  Google Scholar 

  • Jin X., Shearman L. P., Weaver D. R., Zylka M. J., de Vries G. J. and Reppert S. M. 1999 A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68.

    Article  PubMed  CAS  Google Scholar 

  • Kennaway D. J., Varcoe T. J. and Mau V. J. 2003 Rhythmic expression of clock and clock-controlled genes in the rat oviduct. Mol. Hum. Reprod. 9, 503–507.

    Article  PubMed  CAS  Google Scholar 

  • Kennaway D. J., Owens J. A., Voultsios A. and Varcoe T. J. 2006 Functional central rhythmicity and light entrainment, but not liver and muscle rhythmicity, are Clock independent. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, 1172–1180.

    Google Scholar 

  • King D. P., Zhao Y., Sangoram A. M., Wilsbacher L. D., Tanaka M., Antoch M. P. et al. 1997a Positional cloning of the mouse circadian clock gene. Cell 89, 641–653.

    Article  PubMed  CAS  Google Scholar 

  • King D. P., Vitaterna M. H., Chang A. M., Dove W. F., Pinto L. H., Turek F. W. and Takahashi J. S. 1997b The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit. Genetics 146, 1049–1060.

    PubMed  CAS  Google Scholar 

  • Kondratov R. V., Chernov M. V., Kondratova A. A., Gorbacheva V. Y., Gudkov A. V. and Antoch M. P. 2003 BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev. 17, 1921–1932.

    Article  PubMed  CAS  Google Scholar 

  • Kondratov R.V., Kondratova A. A., Lee C., Gorbacheva V. Y., Chernov M. V. and Antoch M. P. 2006 Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by cryptochromes. Cell Cycle 5, 890–895.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kume K., Zylka M. J., Sriram S., Shearman L. P., Weaver D. R., Jin X. et al. 1999 mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lee C., Weaver D. R. and Reppert S. M. 2004 Direct association between mouse PERIOD and CKIepsilon is critical for a functioning circadian clock. Mol. Cell. Biol. 24, 584–594.

    Article  PubMed  CAS  Google Scholar 

  • Liu A. C., Welsh D. K., Ko C. H., Tran H. G., Zhang E. E., Priest A. A. et al. 2007 Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129, 605–616.

    Article  PubMed  CAS  Google Scholar 

  • Liu A. C., Tran H. G., Zhang E. E., Priest A. A., Welsh D. K. and Kay S. A. 2008 Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet. 4, e1000023.

    Google Scholar 

  • Lowrey P. L., Shimomura K., Antoch M. P., Yamazaki S., Zemenides P. D., Ralph M. R. et al. 2000 Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492.

    Article  PubMed  CAS  Google Scholar 

  • Lowrey P. L. and Takahashi J. S. 2004 Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu. Rev. Genomics Hum. Genet. 5, 407–441.

    Article  PubMed  CAS  Google Scholar 

  • Nagoshi E., Saini C., Bauer C., Laroche T., Naef F. and Schibler U. 2004 Circadian gene expression in individual fibroblasts: cellautonomous and self-sustained oscillators pass time to daughter cells. Cell 119, 693–705.

    Article  PubMed  CAS  Google Scholar 

  • Oishi K., Fukui H. and Ishida N. 2000 Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissues. Biochem. Biophys. Res. Commun. 268, 164–171.

    Article  PubMed  CAS  Google Scholar 

  • Oishi K., Miyazaki K. and Ishida N. 2002 Functional CLOCK is not involved in the entrainment of peripheral clocks to the restricted feeding: entrainable expression of mPer2 and BMAL1 mRNAs in the heart of Clock mutant mice on Jcl:ICR background. Biochem. Biophys. Res. Commun. 298, 198–202.

    Article  PubMed  CAS  Google Scholar 

  • Ochi M., Sono S., Sei H., Oishi K., Kobayashi H., Morita Y. and Ishida N. 2003 Sex difference in circadian period of body temperature in Clock mutant mice with Jcl/ICR background. Neurosci. Lett. 347, 163–166.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Preitner N., Damiola F., Lopez-Molina L., Zakany J., Duboule D., Albrecht U. and Schibler U. 2002 The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260.

    Article  PubMed  CAS  Google Scholar 

  • Reick M., Garcia J. A., Dudley C. and McKnight S. L. 2001 NPAS2: an analog of clock operative in the mammalian forebrain. Science 293, 506–509.

    Article  PubMed  CAS  Google Scholar 

  • Reppert S. M. and Weaver D. R. 2002 Coordination of circadian timing in mammals. Nature 418, 935–941.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ripperger J. A. and Schibler U. 2006 Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat. Genet. 38, 369–374.

    Article  PubMed  CAS  Google Scholar 

  • Rutter J., Reick M., Wu L. C. and McKnight S. L. 2001 Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514.

    Article  PubMed  CAS  Google Scholar 

  • Sato T. K., Panda S., Miraglia L. J., Reyes T. M., Rudic R. D., McNamara P. et al. 2004 A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537.

    Article  PubMed  CAS  Google Scholar 

  • Shearman L. P., Zylka M. J., Reppert S. M. and Weaver D. R. 1999 Expression of basic helix-loop-helix/PAS genes in the mouse suprachiasmatic nucleus. Neuroscience 89, 387–397.

    Article  PubMed  CAS  Google Scholar 

  • Silver R., Sookhoo A. I., LeSauter J., Stevens P., Jansen H. T. and Lehman M. N. 1999 Multiple regulatory elements result in regional specificity in circadian rhythms of neuropeptide expression in mouse SCN. Neuroreport 10, 3165–3174.

    Article  PubMed  CAS  Google Scholar 

  • Ueda H. R., Chen W., Adachi A., Wakamatsu H., Hayashi S., Takasugi T. et al. 2002 A transcription factor response element for gene expression during circadian night. Nature 418, 534–539.

    Article  PubMed  CAS  Google Scholar 

  • Ueda H. R., Hayashi S., Chen W., Sano M., Machida M., Shigeyoshi Y. et al. 2005 System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192.

    Article  PubMed  CAS  Google Scholar 

  • Vitaterna M. H., King D. P., Chang A. M., Kornhauser J. M., Lowrey P. L., McDonald J. D. et al. 1994 Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behaviour. Science 264, 719–725.

    Article  PubMed  CAS  Google Scholar 

  • Vitaterna M. H., Ko C. H., Chang A. M., Buhr E. D., Fruechte E. M., Schook A. et al. 2006 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Yoo S. H., Yamazaki S., Lowrey P. L., Shimomura K., Ko C. H., Buhr E. D. 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, 5339–5346.

    Article  PubMed  CAS  Google Scholar 

  • Zhou Y. D., Barnard M., Tian H., Li X., Ring H. Z., Francke U. et al. 1997 Molecular characterization of two mammalian bHLHPAS domain proteins selectively expressed in the central nervous system. Proc. Natl. Acad. Sci. USA 94, 713–718.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 835 BRBII/III, 421 Curie Blvd, Philadelphia, PA, 19104, USA

    Jason P. Debruyne

Authors
  1. Jason P. Debruyne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jason P. Debruyne.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Debruyne, J.P. Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system. J Genet 87, 437–446 (2008). https://doi.org/10.1007/s12041-008-0066-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12041-008-0066-7

Keywords

Search

Navigation