Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau

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

Research output: Contribution to journalArticle

635 Scopus citations

Abstract

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 (CKlε) a homolog of the Drosophila circadian gene double-time. In vitro expression and functional studies of wild-type and tau mutant CKlε enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKlε 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 CKlε and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

Original languageEnglish (US)
Pages (from-to)483-491
Number of pages9
JournalScience
Volume288
Issue number5465
DOIs
StatePublished - Apr 21 2000

ASJC Scopus subject areas

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