CENTER PARTICIPANTS
Joseph S. Takahashi
- Associate Director, Center for Sleep & Circadian Biology
- Walter and Mary Elizabeth Glass Professor in the Life Sciences, Department of Neurobiology and Physiology
- Professor, Department of Neurology, Northwestern University Medical School
- Investigator, Howard Hughes Medical Institute
phone: 847-491-4598
fax: 847-491-4600
Research Interests
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. Our approach to studying the mechanisms of circadian clocks has been threefold: 1) We have developed cellular model systems that express oscillations in vitro. 2) We have analyzed the role of gene expression in the control of circadian rhythms. 3) We have isolated and identified clock mutants in mammals using classical and molecular genetics.
At present, our group is analyzing a number of vertebrate systems that fall into five areas of research: mechanisms of circadian oscillations in chick pineal cells; regulation of melatonin in retinal and retinoblastoma cells; circadian and photic regulation of photoreceptor gene expression; regulation of cellular immediate early genes in the suprachiasmatic nucleus; and molecular genetics of circadian clock mutants in the mouse and hamster.
In future work, we seek to identify the set of genes and gene products involved in the clock mechanism. Among vertebrates this will require the use of model systems such as the mouse that are amenable to molecular genetic approaches. The isolation of clock mutants, the molecular genetic analysis of clock genes, and the creation of immortalized cell lines that express circadian oscillations will ultimately be required to identify elements of the clock system. Once fundamental elements are identified, we will be in a position to analyze the dynamics of the oscillator in order to describe its mechanism.
Selected References:
- Low-Zeddies, S.S., and J.S. Takahashi. (2001) Chimera analysis of the Clock mutation in mice shows that complex cellular integration determines circadian behavior. Cell 105:25-42.
- Nadeau, J.H., R. Balling, G. Barsh, D. Beier, S. D. M. Brown, M. Bucan, S. Camper, G. Carlson, N. Copeland, J. Eppig, C. Fletcher, W.N. Frankel, D. Ganten, D. Goldowitz, C. Goodnow, J.-L. Guenet, G. Hicks, M. Hrabe de Angelis, I. Jackson, H.J. Jacob, N. Jenkins, D. Johnson, M. Justice, S. Kay, D. Kingsley, H. Lehrach, T. Magnuson, M. Meisler, A.M. Poustka, E.M. Rinchik, J. Rossant, L.B. Russell, J. Schimenti, T. Shiroishi, W.C. Skarnes, P. Soriano, W. Stanford, J.S. Takahashi, W. Wurst, and A. Zimmer. (2001) Sequence interpretation: Functional annotation of mouse genome sequences. Science 291:1251-1255.
- Lowrey, P.L. and J.S. Takahashi. (2000) Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Annual Review of Genetics 34:533-562.
- Takahashi, J.S. (1999) Narcolepsy genes wake up the sleep field. Science 285:2076-2077.
- Gekakis, N., D. Staknis, H.B. Nguyen, F.C. Davis, L.D. Wilsbacher, D.P. King, J.S. Takahashi and C.J. Weitz. (1998) Role of the CLOCK protein in the mammalian circadian mechanism. Science 280:1564-1569.
- Darlington, T.K., K. Wager-Smith, M.F. Ceriani, D. Staknis, N. Gekakis, T.D.L. Steeves, C.J. Weitz, J.S. Takahashi and S.A. Kay. (1998) Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280:1599-1603.
- Sangoram, A.M., L. Saez, M.P. Antoch, N. Gekakis, D. Staknis, A. Whiteley, E.M. Fruechte, M.H. Vitaterna, K. Shimomura, D.P. King, M.W. Young, C.J. Weitz and J.S. Takahashi. (1998) Mammalian circadian autoregulatory loop: A Timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron 21:1101-1113.
