title: The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude.
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.
authors.affiliation: Center for Functional Genomics, Center for Sleep and Circadian Biology and Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3520, USA.
authors.forename: Martha Hotz
authors.initials: MH
authors.lastname: Vitaterna
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Ko
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Chang
authors.forename: Ethan D
authors.initials: ED
authors.lastname: Buhr
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Fruechte
authors.forename: Andrew
authors.initials: A
authors.lastname: Schook
authors.forename: Marina P
authors.initials: MP
authors.lastname: Antoch
authors.forename: Fred W
authors.initials: FW
authors.lastname: Turek
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D005786:Gene Expression Regulation; D008027:Light; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D017440:Photoperiod; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D056926:CLOCK Proteins; C538944:Clock protein, mouse