The tau mutation in the Syrian hamster differentially reprograms the circadian clock in the SCN and peripheral tissues
The tau mutation in the Syrian hamster differentially reprograms the circadian clock in the SCN and peripheral tissues
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DOI：
10.1177/0748730404274264
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Maywood, ES
中科院分区：
文献类型：
--
作者：
Dey, J;Carr, AJF;Maywood, ES
下丘脑视交叉上核（SCN）是哺乳动物的主要昼夜节律振荡器，通过明暗循环与太阳日同步，反过来，它们协调外周组织的昼夜节律振荡。叙利亚仓鼠的tau突变是由一个点突变引起的，导致酪蛋白激酶1 epsilon磷酸化其靶标（包括昼夜节律PER蛋白）的能力不足。这如何加速神经组织的昼夜节律尚不清楚，也不清楚它对周围昼夜节律振荡器的影响。我们发现这种突变对SCN中per mRNA的表达和per蛋白的核积累没有影响。然而，它确实加速了细胞核中PER蛋白的清除，其程度足以解释行为节律的昼夜周期缩短。该突变还对周围的昼夜节律时间产生了新的、意想不到的后果，包括组织特异性阶段的进展和/或昼夜节律基因表达幅度的降低。结果表明，tau突变加速了SCN昼夜节律反馈回路的一个特定阶段，而不是导致整个周期的整体压缩。这种来自生物钟的重编程输出与外周不同步有关，这反过来又可以解释突变体的生长和代谢效率受损。
The hypothalamic suprachiasmatic nuclei (SCN), the principal circadian oscillator in mammals, are synchronized to the solar day by the light-dark cycle, and in turn, they coordinate circadian oscillations in peripheral tissues. The tau mutation in the Syrian hamster is caused by a point mutation leading to a deficiency in the ability of Casein Kinase 1 epsilon to phosphorylate its targets, including circadian PER proteins. How this accelerates circadian period in neural tissues is not known, nor is its impact on peripheral circadian oscillators established. We show that this mutation has no effect on per mRNA expression nor the nuclear accumulation of PER proteins in the SCN. It does, however, accelerate the clearance of PER proteins from the nucleus to an extent sufficient to explain the shortened circadian period of behavioral rhythms. The mutation also has novel, unanticipated consequences for circadian timing in the periphery, including tissue-specific phase advances and/or reduced amplitude of circadian gene expression. The results suggest that the tau mutation accelerates a specific phase, during mid-late subjective night of the SCN circadian feedback loop, rather than cause a global compression of the entire cycle. This reprogrammed output from the clock is associated with peripheral desynchrony, which in turn could account for impaired growth and metabolic efficiency of the mutant.