Welcome

Research Interests

The long-term goals of the Takahashi laboratory are to understand the molecular and genetic basis of circadian rhythms in mammals and to utilize forward genetic approaches in the mouse as a tool for gene discovery for complex behavior. We have focused our attention in five areas:

  • Identification of circadian clock genes and assignment of their function in the molecular mechanism of the circadian pacemaker;
  • Analysis of central and peripheral circadian oscillators using real-time circadian reporters;
  • Single-cell analysis of circadian oscillations using bioluminescence imaging methods;
  • In vivo analysis of circadian clock components using tissue-specific and conditional expression of circadian genes in mice; and
  • Identification of genes defined by mutations isolated in the large-scale mutagenesis screens we have conducted on neural and behavioral phenotypes. 

Publications

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

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.

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.

Turek, F.W., C. Joshu, A. Kohsaka, E. Lin, G. Ivanova, E. McDearmon, A. Laposky, S-L. Olson, A. Easton, D.R. Jensen, R.H. Eckel, J.S. Takahashi and J. Bass. 2005. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308:1043-1045.

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.

Vitaterna, M.H., C.H. Ko, A.M. Chang, E.D. Buhr, E.M. Fruechte, A. Schook, M.P. Antoch, F.W. Turek and J.S. Takahashi. 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.

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.

Kornmann, B., O. Schaad, H. Bujard, J.S. Takahashi and U. Schibler. 2007. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biology 5:179-189.

Miller, B.H., E.L. McDearmon, S. Panda, K.R. Hayes, J. Zhang, J.L. Andrews, M.P. Antoch,  J.R. Walker, K.A. Esser, J.B. Hogenesch and J.S. Takahashi. 2007. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc. Natl. Acad. Sci. USA 104:3342-3347.

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.

Liu, A.C. D.K. Welsh, C.H. Ko, H.G. Tran, E.E. Zhang, A.A. Priest, E.D. Buhr, O. Singer, K. Meeker, I.M. Verma, F.J. Doyle, J.S. Takahashi and S.A Kay. 2007. Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129:605-616.

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 129:1011-1023.

O’Neil, J.S., E.S. Maywood, J.E. Chesham, J.S. Takahashi and M.H. Hastings. 2008. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320:949-953.

Green, C.B., J.S. Takahashi and J. Bass. 2008. The meter of metabolism. Cell 134:728-742.

Takahashi, J.S., H.-K. Hong, C.H. Ko and E.L. McDearmon. 2008. The genetics of mammalian circadian order and disorder: Implications for physiology and disease. Nature Reviews Genetics 9:764-775

Takahashi, J.S., K. Shimomura and V. Kumar. 2008. Searching for genes underlying behavior: Lessons from circadian rhythms. Science 322:909-912.

Ramsey, K.M., J. Yoshino, C.S. Brace, D. Abrassart, Y. Kobayashi, B. Marcheva, H.K. Hong, J.L. Chong, E.D. Buhr, C. Lee, J.S. Takahashi, S. Imai and J. Bass. Circadian clock feedback through NAMPT-mediated NAD biosynthesis. Science 324:651-654.

Significant Publications

Vitaterna, M.H., D.P. King, A.-M. Chang, J.M. Kornhauser, P.L. Lowrey, J.D. McDonald, W.F. Dove, L.H. Pinto, F.W. Turek and J.S. Takahashi. 1994. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264:719-725.

King, D.P., Y. Zhao, A.M. Sangoram, L.D. Wilsbacher, M. Tanaka, M.P. Antoch, T.D.L. Steeves, M.H. Vitaterna, J.M. Kornhauser, P.L. Lowrey, F.W. Turek and J.S. Takahashi. 1997. Positional cloning of the mouse circadian Clock gene. Cell 89:641-653.

Antoch, M.P., E.-J. Song, A.-M. Chang, M.H. Vitaterna, Y. Zhao, L.D. Wilsbacher, A.M. Sangoram, D.P. King, L.H. Pinto and J.S. Takahashi. 1997. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 89:655-667.

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.

Lowrey, P.L., K. Shimomura, M.P. Antoch, S. Yamazaki, P.D. Zemenides, M.R. Ralph, M. Menaker and J.S. Takahashi. 2000. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288:483-491.

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.

Panda, S., M.P. Antoch, B.H. Miller, A.I. Su, A.B. Schook, M. Straume, P.G. Schultz, S.A. Kay, J.S. Takahashi and J.B. Hogenesch. 2002. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109:307-320.

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.

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.

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 129:1011-1023.

Educational Background

Joseph Takahashi, MD, is Chair of the Department of Neuroscience and an Investigator of the Howard Hughes Medical Institute at UT Southwestern. He currently holds the Loyd B. Sands Distinguished Chair in Neuroscience. Dr. Takahashi received a BA in biology from Swarthmore College in 1974 and a PhD in neuroscience from the University of Oregon, Eugene, in 1981. For postdoctoral training, he was a pharmacology research associate at the National Institute of Mental Health from 1981-1983.

Dr. Takahashi has pioneered the use of forward genetics and positional cloning in the mouse as a tool for discovery of genes underlying neurobiology and behavior, and his discovery of the mouse and human clock genes led to a description of a conserved circadian clock mechanism in animals.