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Study of DNA repair deficient mice

DNA修复缺陷小鼠的研究

基本信息

批准号：
10044231
负责人：
YASUI Akira
金额：
$ 4.48万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

We isolated two mouse homologues of photolyase gene (mCry1 and mCry2), which encode proteins in the family of blue-light receptors. To explore the biological function of mammalian Cry1 and Cry2, we have generated cry1 and cry2 mutant mice through gene targeting in embryonic stem cells. Since these mutant mice are completely healthy and showed no overt phenotype, we analyzed the possible role for CRY proteins in the biological clock by measuring the circadian wheel-running behavior of cry-knockout mice under normal light/dark (LD) cycles and in constant darkness (DD). Since CRY proteins are able to function as blue-light receptor, these protein may be involved in the light entrainment ability. We found that mice lacking the Cry1 or Cry2 protein display accelerated and delayed free-running (DD) periodicity of locomotor activity, respectively. These findings suggest that Cry1 and Cry2 antagonistically modulate the period length of the clock. Above results indicate, however, that a deficiency in either gene does not produce a detectable loss of light entrainment of locomotor activity. Since cry1 mouse still contain a functional Cry2 protein, we generated double-mutant animals. To our surprise, in the absence of both proteins, an instantaneous and complete loss of free-running rhythmicity is observed. This suggests that, in addition to a possible photoreceptor and antagonistic clock-adjusting function, both proteins are essential for the maintenance of circadian rhytjmicity.

我们分离了两个小鼠的光解酶基因同源基因(mCry1和mCry2)，它们编码蓝光受体家族的蛋白。为了探索哺乳动物Cry1和Cry2的生物学功能，我们在胚胎干细胞中通过基因打靶获得了突变的Cry1和Cry2小鼠。由于这些突变小鼠是完全健康的，没有明显的表型，我们通过测量哭泣基因敲除小鼠在正常光/暗(LD)周期和恒定黑暗(DD)周期下的昼夜轮子运行行为，分析了CORT蛋白在生物时钟中的可能作用。由于CRY蛋白能够作为蓝光受体发挥作用，这些蛋白可能参与了光携带的能力。我们发现，缺乏Cry1或Cry2蛋白的小鼠表现出运动活动的加速和延迟的自由奔跑(DD)周期。这些发现表明，Cry1和Cry2拮抗地调节了时钟的周期长度。然而，上述结果表明，任何一个基因的缺失都不会导致可检测到的运动活动光夹带的损失。由于Cry1小鼠仍然含有功能性的Cry2蛋白，因此我们培育了双突变动物。令我们惊讶的是，在没有这两种蛋白质的情况下，观察到自由奔跑节律性的瞬间和完全丧失。这表明，除了可能的光感受器和拮抗性时钟调节功能外，这两种蛋白对维持昼夜节律是必不可少的。