Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice
Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice
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DOI：
10.1126/science.1132430
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发表时间：
2006-11-24
期刊：
影响因子：
56.9
通讯作者：
Takahashi, Joseph S.
中科院分区：
文献类型：
--
作者：
McDearmon, Erin L.;Patel, Kush N.;Takahashi, Joseph S.
碱性螺旋-环-螺旋（bHLH）- Per-Arnt-Sim（PAS）结构域转录因子BMAL 1是哺乳动物昼夜节律起搏器的重要组成部分。Bmal 1（-/-）小鼠失去昼夜节律，但也显示肌腱钙化和活动减少，体重和寿命。为了研究BMAL 1的这些不同功能是否是组织特异性的，我们产生了在大脑或肌肉中组成型表达Bmal 1的转基因小鼠，并检查了Bmal 1（-/-）小鼠中拯救基因表达的影响。在脑拯救的Bmal 1（-/-）小鼠中，以有条件的方式恢复了轮跑活动的昼夜节律;然而，活动水平和体重低于野生型小鼠。相比之下，肌肉拯救的Bmal 1（-/-）小鼠表现出正常的活动水平和体重，但仍保持行为异常。因此，Bmal 1具有独特的组织特异性功能，调节综合生理学。
The basic helix-loop-helix ( bHLH) - Per-Arnt-Sim ( PAS) domain transcription factor BMAL1 is an essential component of the mammalian circadian pacemaker. Bmal1(-/-) mice lose circadian rhythmicity but also display tendon calcification and decreased activity, body weight, and longevity. To investigate whether these diverse functions of BMAL1 are tissue-specific, we produced transgenic mice that constitutively express Bmal1 in brain or muscle and examined the effects of rescued gene expression in Bmal1(-/-) mice. Circadian rhythms of wheel-running activity were restored in brain-rescued Bmal1(-/-) mice in a conditional manner; however, activity levels and body weight were lower than those of wild-type mice. In contrast, muscle-rescued Bmal1(-/-) mice exhibited normal activity levels and body weight yet remained behaviorally arrhythmic. Thus, Bmal1 has distinct tissue-specific functions that regulate integrative physiology.