The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude

Martha Hotz Vitaterna, Caroline H. Ko, Anne Marie Chang, Ethan D. Buhr, Ethan M. Fruechte, Andrew Schook, Marina P. Antoch, Fred W. Turek, Joseph S. Takahashi

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

The mouse Clock gene encodes a basic helix-loop-helix-PAS transcription factor, CLOCK, that acts in concert with BMAL1 to form the positive elements of the circadian clock mechanism in mammals. The original Clock mutant allele is a dominant negative (antimorphic) mutation that deletes exon 19 and causes an internal deletion of 51 aa in the C-terminal activation domain of the CLOCK protein. Here we report that heterozygous Clock/+ mice exhibit high-amplitude phase-resetting responses to 6-h light pulses (Type 0 resetting) as compared with wild-type mice that have low amplitude (Type 1) phase resetting. The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes. Per1 and Per2, are not affected by the Clock/+ mutation. However, the amplitude of the circadian rhythms of Per gene expression are significantly reduced in Clock homozygous and heterozygous mutants. Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in Clock heterozygotes. The phase-response curves to changes in culture medium are Type 0 in Clock heterozygotes, but Type 1 in wild types, similar to that seen for light in vivo. The increased efficacy of resetting stimuli and decreased PER expression amplitude can be explained in a unified manner by a model in which the Clock mutation reduces circadian pacemaker amplitude in the suprachiasmatic nuclei.

Original languageEnglish (US)
Pages (from-to)9327-9332
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number24
DOIs
StatePublished - Jun 13 2006

Keywords

  • Circadian clock
  • Clock gene entrainment
  • Per genes
  • Suprachiasmatic nucleus

ASJC Scopus subject areas

  • General

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