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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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