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Molecular neurobiology and genetics of circadian clocks

The long-term objective of the research in our laboratory is to understand the cellular and molecular mechanisms that regulate circadian rhythms. We have initiated a genetic approach to study the mechanism of circadian rhythms in mammals using the mouse as a model organism.

In a deliberate chemical mutagenesis screen for circadian rhythm mutants, we isolated the first circadian mutation in mice, Clock. The Clock mutation is semidominant and lengthens circadian period by 1 hr in heterozygotes and by 4 hr in homozygotes. Importantly Clock homozygotes lose persistent circadian rhythms in constant darkness.

Further work identified three additional genes which, when combined with Clock, define a basic framework for a transciptional autoregulatory mechanism that appears to compose the circadian oscillator mechanism in animals. The delineation of this circadian gene pathway should eventually lead to an understanding of how circadian clocks function and their environmental regulation.

• Takahashi JS, Shimomura K, Kumar V. (2008) Searching for genes underlying behavior: lessons from circadian rhythms. Science. 322(5903):909-12.

• Takahashi JS, Hong HK, Ko CH, McDearmon EL. (2008) The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet. 9(10):764-75. Review.

• Green CB, Takahashi JS, Bass J. (2008) The meter of metabolism. Cell. 2008 Sep 5;134(5):728-42. Review.

• O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. (2008) cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science. 320(5878):949-53.

• Wu C, Delano DL, Mitro N, Su SV, Janes J, McClurg P, Batalov S, Welch GL, Zhang J, Orth AP, Walker JR, Glynne RJ, Cooke MP, Takahashi JS, Shimomura K, Kohsaka A, Bass J, Saez E, Wiltshire T, Su AI. (2008) Gene set enrichment in eQTL data identifies novel annotations and pathway regulators. PLoS Genet. 4(5):e1000070.

• Meng QJ, Logunova L, Maywood ES, Gallego M, Lebiecki J, Brown TM, Sládek M, Semikhodskii AS, Glossop NR, Piggins HD, Chesham JE, Bechtold DA, Yoo SH, Takahashi JS, Virshup DM, Boot-Handford RP, Hastings MH, Loudon AS. (2008) Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron. 58(1):78-88.

• Siepka, S.M., S.-H. Yoo, J. Park, W. Song, V. Kumar, Y. Hu, C. Lee and J.S. Takahashi. 2007. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell doi:10.10/16/jcell.2007.04.030.

• Hong, H-K., J.L. Chong, W. Song, E.J. Song, A.A. Jyawook, A.C. Schook, C.H. Ko and J.S. Takahashi. 2007. Inducible and reversible Clock gene expression in brain using the tTA system for the study of circadian behavior. PLoS Genetics 3:324-338 [3(2): e33. doi:10.1371/journal.pgen.0030033].

• McDearmon, E.L., K.N. Patel, C.H. Ko, J.A. Walisser, A.C. Schook, J.L. Chong, L.D. Wilsbacher, E-J Song, H-K Hong, C.A. Bradfield, and J.S. Takahashi. 2006.  Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice.  Science 314:1304-1308.

• Vitaterna, M.H., L.H. Pinto and J.S. Takahashi. 2006. Large-scale mutagenesis and phenotypic screens for the nervous system and behavior in mice. Trends in Neuroscience 29:233-240.

• Gorbacheva, V.Y., R.V. Kondratov, R. Zhang, S. Cherukuri, A.V. Gudkov, J.S. Takahashi and M.P. Antoch. 2005. Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex.  Proc. Natl. Acad. Sci. USA 102:3407-3412.

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

• Takahashi, J.S. 2004. Finding new clock components: Past and future. Journal of Biological Rhythms 19:339-347.

• Lowrey, P.L. and J.S. Takahashi. 2004. Mammalian circadian biology: Elucidating genome-wide levels of temporal organization. Annual Review of Genomics and Human Genetics  5:407-441.

• Yoo, S.-H., S. Yamazaki, P.L. Lowrey, K. Shimomura, C.H. Ko, E.D. Buhr, S.M. Siepka, H.-K. Hong, W.-J. Oh, O.-J. Yoo, M. Menaker and J.S. Takahashi. 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.

Other Links:

• link to a more detailed research description

• Dr. Takahashi's Howard Hughes Medical Institute (HHMI) page

• Center for Circadian Biology and Medicine (CCBM) at Northwestern University

• Center for Functional Genomics

• NeuroMice.org