Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2
Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2
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DOI：
10.1073/pnas.96.21.12114
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发表时间：
1999-10-12
影响因子：
11.1
通讯作者：
Sancar, A
中科院分区：
文献类型：
--
作者：
Vitaterna, MH;Selby, CP;Sancar, A
隐花色素调节动植物的生物钟。人类和小鼠都有两个隐色素(Cry)基因。先前的一项研究表明，缺乏Cry2基因的小鼠对视交叉上核(SCN)中昼夜节律基因mper1的急性光诱导敏感性降低，并且固有周期比正常长1小时。在本研究中，建立了Cry1(-/-)和Cry1(-/-)Cry2(-/-)小鼠，并从行为和分子水平分析了它们的昼夜节律对接。在行为学上，Cry1(-/-)小鼠的昼夜节律周期比野生型小鼠短1小时，而Cry1(-/-)Cry2(-/-)小鼠在持续黑暗(DD)中出现心律失常。在生物化学方面，在Cry1(-/-)小鼠的SCN中，急性光诱导的mPer1mRNA被钝化，而在Cry1(-/-)Cry2(-/-)小鼠中则被取消。相反，在Cry1(-/-)和Cry1(-/-)Cry2(-/-)动物中，SCN中mPer2的急性光诱导是完整的。重要的是，在双突变体中，mPer1的表达呈结构性升高，在12小时光照/12小时黑暗或DD中都没有检测到节律性，而mPer2在12小时光照/12小时黑暗中表现出节律性，但在中等水平的DD中表现为非节律性。这些结果表明，Cry1和Cry2是SCN正常表达昼夜行为节律以及mPer1和mPer2昼夜节律所必需的。在Cry双突变体中，光对mPer1和mPer2的不同调控揭示了隐花色素在哺乳动物中作用的惊人复杂性。
Cryptochromes regulate the circadian clock in animals and plants. Humans and mice have two cryptochrome (Cry) genes. A previous study showed that mice lacking the Cry2 gene had reduced sensitivity to acute light induction of the circadian gene mPer1 in the suprachiasmatic nucleus (SCN) and had an intrinsic period 1 hr longer than normal. In this study, Cry1(-/-) and Cry1(-/-)Cry2(-/-) mice were generated and their circadian docks were analyzed at behavioral and molecular levels. Behaviorally, the Cry1(-/-) mice had a circadian period 1 hr shorter than wild type and the Cry1(-/-)Cry2(-/-) mice were arrhythmic in constant darkness (DD). Biochemically, acute light induction of mPer1 mRNA in the SCN was blunted in Cry1(-/-) and abolished in Cry1(-/-)Cry2(-/-) mice. In contrast, the acute light induction of mPer2 in the SCN was intact in Cry1(-/-) and Cry1(-/-)Cry2(-/-) animals. Importantly, in double mutants, mPer1 expression was constitutively elevated and no rhythmicity was detected in either 12-hr light/12-hr dark or DD, whereas mPer2 expression appeared rhythmic in 12-hr light/12-hr dark, but nonrhythmic in DD with intermediate levels. These results demonstrate that Cry1 and Cry2 are required for the normal expression of circadian behavioral rhythms, as well as circadian rhythms of mPer1 and mPer2 in the SCN. The differential regulation of mPer1 and mPer2 by light in Cry double mutants reveals a surprising complexity in the role of cryptochromes in mammals.