The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude
The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude
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DOI：
10.1073/pnas.0603601103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Takahashi, Joseph S.
中科院分区：
文献类型：
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作者：
Vitaterna, Martha Hotz;Ko, Caroline H.;Takahashi, Joseph S.
小鼠Clock基因编码一个基本的螺旋-环-螺旋-PAS转录因子CLOCK，它与BMAL 1协同作用，形成哺乳动物生物钟机制的阳性元件。原始的Clock突变等位基因是显性负性（反形）突变，其缺失外显子19并导致CLOCK蛋白的C末端激活结构域中的51个氨基酸的内部缺失。在这里，我们报告说，杂合子时钟/+小鼠表现出高振幅的相位复位响应6小时的光脉冲（0型复位）相比，野生型小鼠具有低振幅（1型）相位复位。急性光诱导的幅度和时间过程中的视交叉上核的唯一已知的光诱导的核心时钟基因，Per 1和Per 2，不受时钟/+突变。然而，在Clock纯合子和杂合子突变体中，Per基因表达的昼夜节律的幅度显著降低。PER 2：：荧光素酶在视交叉上核外植体培养物中表达的节律在Clock杂合子中的幅度也降低。对培养基变化的相位响应曲线在Clock杂合子中为0型，但在野生型中为1型，与体内光的变化相似。重置刺激的功效增加和PER表达幅度降低可以通过一个模型以统一的方式来解释，在该模型中，Clock突变降低了视上核中的昼夜节律起搏器幅度。
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 suprackiasmatic nuclei.