Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice
Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice
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DOI：
10.1101/gad.233702
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发表时间：
2002-10-15
影响因子：
10.5
通讯作者：
Albrecht, U
中科院分区：
文献类型：
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作者：
Oster, H;Yasui, A;Albrecht, U
许多生化、生理和行为过程都显示出由称为生物钟的内部计时机制产生的每日节律。驱动该时钟的核心振荡器位于下丘脑的腹侧部分，即所谓的视交叉上核（SCN）。在分子水平上，这种振荡器被认为是由涉及一组时钟基因的连锁自动调节反馈回路组成。驱动哺乳动物生物钟的成分包括周期 1 和周期 2（mPer1 和 mPer2）以及隐花色素 1 和 2（mCry1 和 mCry2）基因。 mPer2 基因突变会导致持续黑暗 (DD) 小鼠的昼夜节律逐渐丧失。在这里，我们证明 mPer2 突变小鼠中 mCry2 基因的失活可以恢复昼夜节律和正常的时钟基因表达模式。因此，mCry2 可以充当 mPer2 的非等位基因抑制因子，这表明 PER2 和 CRY2 蛋白有直接或间接的相互作用。与此形成鲜明对比的是，mPer2突变小鼠中mCry1的失活并不能恢复昼夜节律，而是导致DD完全行为心律失常，表明mCry1和mCry2在时钟机制中的不同作用。
Many biochemical, physiological, and behavioral processes display daily rhythms generated by an internal timekeeping mechanism referred to as the circadian clock. The core oscillator driving this clock is located in the ventral part of the hypothalamus, the so called suprachiasmatic nuclei (SCN). At the molecular level, this oscillator is thought to be composed of interlocking autoregulatory feedback loops involving a set of clock genes. Among the components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) and Cryptochrome 1 and 2 (mCry1 and mCry2) genes. A mutation in the mPer2 gene leads to a gradual loss of circadian rhythmicity in mice kept in constant darkness (DD). Here we show that inactivation of the mCry2 gene in mPer2 mutant mice restores circadian rhythmicity and normal clock gene expression patterns. Thus, mCry2 can act as a nonallelic suppressor of mPer2, which points to direct or indirect interactions of PER2 and CRY2 proteins. In marked contrast, inactivation of mCry1 in mPer2 mutant mice does not restore circadian rhythmicity but instead results in complete behavioral arrhythmicity in DD, indicating different effects of mCry1 and mCry2 in the clock mechanism.