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Science 21 April 2000:
Vol. 288. no. 5465, pp. 483 - 491
DOI: 10.1126/science.288.5465.483
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Research Articles

Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau

Phillip L. Lowrey, 1 Kazuhiro Shimomura, 12 Marina P. Antoch, 12 Shin Yamazaki, 3 Peter D. Zemenides, 1 Martin R. Ralph, 4 Michael Menaker, 3 Joseph S. Takahashi 12*

The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIepsilon ), a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKIepsilon enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIepsilon can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIepsilon and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

1 Department of Neurobiology and Physiology,
2 Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
3 Department of Biology, National Science Foundation Center for Biological Timing, University of Virginia, Charlottesville, VA 22903, USA.
4 Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
*   To whom correspondence should be addressed. E-mail: j-takahashi{at}northwestern.edu

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Oscillating on Borrowed Time: Diffusible Signals from Immortalized Suprachiasmatic Nucleus Cells Regulate Circadian Rhythmicity in Cultured Fibroblasts.
G. Allen, J. Rappe, D. J. Earnest, and V. M. Cassone (2001)
J. Neurosci. 21, 7937-7943
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Science. ISSN 0036-8075 (print), 1095-9203 (online)