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Gene Review

Clock  -  circadian locomotor output cycles kaput

Mus musculus

Synonyms: 5330400M04Rik, Circadian locomoter output cycles protein kaput, KAT13D, bHLHe8, mCLOCK, ...
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Disease relevance of Clock

  • The amount of milk secreted from dams, as calculated by the increase in pup body weight through suckling, was lower in Clock-mutant mothers vs. wild-type mice [1].
  • We therefore showed that a Clock mutation attenuates obesity induced by a high-fat diet in mice with an ICR background through impaired dietary fat absorption [2].
  • We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia [3].
  • With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans [4].

Psychiatry related information on Clock

  • Long-term, multielectrode recordings showed that heterozygous Clock mutant neurons have lengthened periods and that homozygous Clock neurons are arrhythmic, paralleling the effects on locomotor activity in the animal [5].
  • The present results demonstrate that Clock mutation disrupts daily maternal behavior and the growth and survival rate of pups, especially with the breeding of more than 10 pups [1].
  • The human Clock gene has been proposed as a possible candidate for disorders affected by alterations of circadian rhythm, including bipolar disorder and schizophrenia [6].
  • These data indicate that the Clock mutation leads to increased exploratory behavior and increased escape-seeking behavior, and, conversely, does not result in increased anxiety or depressive-like behavior [7].
  • The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12 [8].

High impact information on Clock

  • The Clock mutation lengthens periodicity and reduces amplitude of circadian rhythms in mice [9].
  • The effects of Clock are cell intrinsic and can be observed at the level of single neurons in the suprachiasmatic nucleus [9].
  • Significantly, a number of intermediate phenotypes, including Clock/+ phenocopies and novel combinations of the parental behavioral characteristics, were seen in balanced chimeras [9].
  • To address how cells of contrasting genotype functionally interact in vivo to control circadian behavior, we have analyzed a series of Clock mutant mouse aggregation chimeras [9].
  • These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK [10].

Biological context of Clock


Anatomical context of Clock


Associations of Clock with chemical compounds

  • Nevertheless, the SCN of Clock(Delta19) + MEL mutant mice cannot maintain liver and muscle rhythmicity through rhythmic outputs, including melatonin secretion, in the absence of functional Clock expression in the tissues [19].
  • Clock, a mammalian clock gene encoding a PAS-containing polypeptide, has now been cloned: it is likely that the Per homologues dimerize with other molecule(s) such as Clock through PAS-PAS interaction in the circadian clock system [20].
  • Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype [21].
  • Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained [21].
  • Regulation of dopaminergic transmission and cocaine reward by the Clock gene [22].

Regulatory relationships of Clock

  • Involvement of circadian clock gene Clock in diabetes-induced circadian augmentation of plasminogen activator inhibitor-1 (PAI-1) expression in the mouse heart [23].

Other interactions of Clock

  • The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation [12].
  • Similar to changes in molecular and physiological rhythmicity observed in the SCN of Clock mutant mice, the rhythmic pattern of Per2 expression was disrupted and the period of metabolic rhythmicity was increased in SCN2.2 cells subjected to antisense inhibition of Clock [13].
  • Genetically linked to the molecular oscillator, it was identified as a repressor of the Bmal1 and Clock genes [24].
  • Restricted feeding induces daily expression of clock genes and Pai-1 mRNA in the heart of Clock mutant mice [25].
  • A robust attenuation of the Dec1 and Dec2 signals in Clock mutant mice was detected in all brain areas examined [26].

Analytical, diagnostic and therapeutic context of Clock


  1. Circadian Clock mutation in dams disrupts nursing behavior and growth of pups. Hoshino, K., Wakatsuki, Y., Iigo, M., Shibata, S. Endocrinology (2006) [Pubmed]
  2. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. Oishi, K., Atsumi, G., Sugiyama, S., Kodomari, I., Kasamatsu, M., Machida, K., Ishida, N. FEBS Lett. (2006) [Pubmed]
  3. Obesity and metabolic syndrome in circadian Clock mutant mice. Turek, F.W., Joshu, C., Kohsaka, A., Lin, E., Ivanova, G., McDearmon, E., Laposky, A., Losee-Olson, S., Easton, A., Jensen, D.R., Eckel, R.H., Takahashi, J.S., Bass, J. Science (2005) [Pubmed]
  4. Circadian rhythms and reproduction. Boden, M.J., Kennaway, D.J. Reproduction (2006) [Pubmed]
  5. Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Herzog, E.D., Takahashi, J.S., Block, G.D. Nat. Neurosci. (1998) [Pubmed]
  6. The polyglutamine motif is highly conserved at the Clock locus in various organisms and is not polymorphic in humans. Saleem, Q., Anand, A., Jain, S., Brahmachari, S.K. Hum. Genet. (2001) [Pubmed]
  7. The circadian Clock mutation increases exploratory activity and escape-seeking behavior. Easton, A., Arbuzova, J., Turek, F.W. Genes Brain Behav. (2003) [Pubmed]
  8. The circadian clock mutation alters sleep homeostasis in the mouse. Naylor, E., Bergmann, B.M., Krauski, K., Zee, P.C., Takahashi, J.S., Vitaterna, M.H., Turek, F.W. J. Neurosci. (2000) [Pubmed]
  9. Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior. Low-Zeddies, S.S., Takahashi, J.S. Cell (2001) [Pubmed]
  10. Mop3 is an essential component of the master circadian pacemaker in mammals. Bunger, M.K., Wilsbacher, L.D., Moran, S.M., Clendenin, C., Radcliffe, L.A., Hogenesch, J.B., Simon, M.C., Takahashi, J.S., Bradfield, C.A. Cell (2000) [Pubmed]
  11. NPAS2: an analog of clock operative in the mammalian forebrain. Reick, M., Garcia, J.A., Dudley, C., McKnight, S.L. Science (2001) [Pubmed]
  12. The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude. Vitaterna, M.H., Ko, C.H., Chang, A.M., Buhr, E.D., Fruechte, E.M., Schook, A., Antoch, M.P., Turek, F.W., Takahashi, J.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Effects of altered Clock gene expression on the pacemaker properties of SCN2.2 cells and oscillatory properties of NIH/3T3 cells. Allen, G.C., Farnell, Y., Bell-Pedersen, D., Cassone, V.M., Earnest, D.J. Neuroscience (2004) [Pubmed]
  14. Melatonin plays a crucial role in the regulation of rhythmic clock gene expression in the mouse pars tuberalis. VON Gall, C., Weaver, D.R., Moek, J., Jilg, A., Stehle, J.H., Korf, H.W. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
  15. The mouse Clock locus: sequence and comparative analysis of 204 kb from mouse chromosome 5. Wilsbacher, L.D., Sangoram, A.M., Antoch, M.P., Takahashi, J.S. Genome Res. (2000) [Pubmed]
  16. No circadian rhythms in testis: Period1 expression is clock independent and developmentally regulated in the mouse. Morse, D., Cermakian, N., Brancorsini, S., Parvinen, M., Sassone-Corsi, P. Mol. Endocrinol. (2003) [Pubmed]
  17. Circadian expression of clock genes in purified hematopoietic stem cells is developmentally regulated in mouse bone marrow. Tsinkalovsky, O., Filipski, E., Rosenlund, B., Sothern, R.B., Eiken, H.G., Wu, M.W., Claustrat, B., Bayer, J., Lévi, F., Laerum, O.D. Exp. Hematol. (2006) [Pubmed]
  18. Clock gene expression in the submandibular glands. Furukawa, M., Kawamoto, T., Noshiro, M., Honda, K.K., Sakai, M., Fujimoto, K., Honma, S., Honma, K., Hamada, T., Kato, Y. J. Dent. Res. (2005) [Pubmed]
  19. Functional central rhythmicity and light entrainment, but not liver and muscle rhythmicity, are Clock independent. Kennaway, D.J., Owens, J.A., Voultsios, A., Varcoe, T.J. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  20. Circadian oscillation of a mammalian homologue of the Drosophila period gene. Tei, H., Okamura, H., Shigeyoshi, Y., Fukuhara, C., Ozawa, R., Hirose, M., Sakaki, Y. Nature (1997) [Pubmed]
  21. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. Rudic, R.D., McNamara, P., Curtis, A.M., Boston, R.C., Panda, S., Hogenesch, J.B., Fitzgerald, G.A. PLoS Biol. (2004) [Pubmed]
  22. Regulation of dopaminergic transmission and cocaine reward by the Clock gene. McClung, C.A., Sidiropoulou, K., Vitaterna, M., Takahashi, J.S., White, F.J., Cooper, D.C., Nestler, E.J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  23. Involvement of circadian clock gene Clock in diabetes-induced circadian augmentation of plasminogen activator inhibitor-1 (PAI-1) expression in the mouse heart. Oishi, K., Ohkura, N., Amagai, N., Ishida, N. FEBS Lett. (2005) [Pubmed]
  24. Mapping of binding regions for the circadian regulators BMAL1 and CLOCK within the mouse Rev-erbalpha gene. Ripperger, J.A. Chronobiol. Int. (2006) [Pubmed]
  25. Restricted feeding induces daily expression of clock genes and Pai-1 mRNA in the heart of Clock mutant mice. Minami, Y., Horikawa, K., Akiyama, M., Shibata, S. FEBS Lett. (2002) [Pubmed]
  26. Dec1 and Dec2 expression is disrupted in the suprachiasmatic nuclei of Clock mutant mice. Butler, M.P., Honma, S., Fukumoto, T., Kawamoto, T., Fujimoto, K., Noshiro, M., Kato, Y., Honma, K. J. Biol. Rhythms (2004) [Pubmed]
  27. Rhythmic expression of BMAL1 mRNA is altered in Clock mutant mice: differential regulation in the suprachiasmatic nucleus and peripheral tissues. Oishi, K., Fukui, H., Ishida, N. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  28. Clock mutation lengthens the circadian period without damping rhythms in individual SCN neurons. Nakamura, W., Honma, S., Shirakawa, T., Honma, K. Nat. Neurosci. (2002) [Pubmed]
  29. Suprachiasmatic nucleus grafts restore circadian behavioral rhythms of genetically arrhythmic mice. Sujino, M., Masumoto, K.H., Yamaguchi, S., van der Horst, G.T., Okamura, H., Inouye, S.T. Curr. Biol. (2003) [Pubmed]
  30. The role of Clock in the developmental expression of neuropeptides in the suprachiasmatic nucleus. Herzog, E.D., Grace, M.S., Harrer, C., Williamson, J., Shinohara, K., Block, G.D. J. Comp. Neurol. (2000) [Pubmed]
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