The mouse <i>Clock</i> mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude

• Martha Hotz Vitaterna

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Caroline H. Ko

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Anne-Marie Chang

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Ethan D. Buhr

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Ethan M. Fruechte

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Andrew Schook

  Howard Hughes Medical Institute, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520; and

• Marina P. Antoch

  Howard Hughes Medical Institute, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520; and

• Fred W. Turek

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

• Joseph S. Takahashi

  *Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology,

抄録

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.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 103 (24), 9327-9332, 2006-06-13

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1362262945129057792
• NII論文ID: 80019093957
• DOI: 10.1073/pnas.0603601103
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.0603601103
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