Oster Henrik, van der Horst Gijsbertus T J, Albrecht Urs
Department of Medicine, Division of Biochemistry, University of Fribourg, Fribourg, Switzerland.
Chronobiol Int. 2003 Jul;20(4):683-95. doi: 10.1081/cbi-120022408.
The mammalian central pacemaker, driving circadian rhythms in behavior, physiology, and metabolism, is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. At the molecular level circadian clocks are based on a system of transcriptional/translational feedback loops oscillating with a period of about 24h. In mammals the CLOCK/BMAL1 transcriptional activator complex regulates a set of central clock genes like mPer1, mPer2, mCry1, and mCry2. The corresponding gene products form protein complexes that translocate into the nucleus and inhibit CLOCK/BMAL1-driven transcription of their own genes and other E-box containing genes. To elucidate whether only one of these four genes of the negative feedback loop is sufficient to generate a 24h rhythm we generated mPer/mCry triple mutant mice. As could be expected on the basis of the arrhythmicity of mPer1/mPer2 and mCry1/mCry2 double mutant mice, we show that none of the triple mutants is able to maintain circadian rhythmicity in constant darkness. This indicates that a single mPer or mCry gene is not sufficient to drive circadian rhythms. Interestingly however, under light-dark conditions (LD) the oscillation of some output genes is persisting in these animals indicating that the LD cycle is able to partially drive rhythmic signalling to the body, through an hour-glass mechanism.
驱动行为、生理和新陈代谢昼夜节律的哺乳动物中央起搏器位于下丘脑的视交叉上核（SCN）。在分子水平上，生物钟基于一个转录/翻译反馈环系统，该系统以约24小时的周期振荡。在哺乳动物中，CLOCK/BMAL1转录激活复合物调节一组核心生物钟基因，如mPer1、mPer2、mCry1和mCry2。相应的基因产物形成蛋白质复合物，这些复合物易位进入细胞核，并抑制CLOCK/BMAL1驱动的自身基因和其他含E-box基因的转录。为了阐明负反馈环中的这四个基因中是否只有一个足以产生24小时节律，我们构建了mPer/mCry三突变小鼠。基于mPer1/mPer2和mCry1/mCry2双突变小鼠的无节律性，可以预期，我们发现所有三突变体在持续黑暗中均无法维持昼夜节律。这表明单个mPer或mCry基因不足以驱动昼夜节律。然而，有趣的是，在光暗条件（LD）下，这些动物中一些输出基因的振荡持续存在，这表明LD周期能够通过沙漏机制部分驱动向身体的节律性信号传导。
