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PER2 controls circadian periods through nuclear localization in the suprachiasmatic nucleus

机译:PER2通过视交叉上核中的核定位来控制昼夜节律

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摘要

Molecular circadian clock regulation engages a negative feedback loop comprising components of the negative limb, PERs and CRYs. In addition to the rhythmic transcriptional regulation of clock genes, controlled subcellular localization might contribute to the molecular mechanism of the mammalian circadian clock. To address this issue, we generated transgenic (TG) mice lines harboring either rat PER2 (rPER2) with a deleted nuclear localizing domain [NLD(-)] or intact PER2. In comparison with wild-type (WT) control, the period of the circadian locomotor rhythm in TG mice over-expressing NLD(-) PER2 was longer, while that in TG mice over-expressing intact PER2 was shorter. The nuclear entry of endogenous PER2, CRY1 and CRY2 was delayed in the suprachiasmatic nucleus (SCN) of NLD(-) PER2 TG mice under constant darkness, whereas that of mouse PER2 (mPER2) is accelerated in the SCN of intact PER2 TG mice. Under constant light, the locomotor activity of NLD(-) PER2 TG mice became arrhythmic, whereas WT animals remained rhythmic. These data indicate that PER2 controls circadian periods through nuclear localization in the SCN. In addition, sleep architecture was also affected in intact PER2 TG mice, suggesting PER2 can modulate a sleep molecular mechanism.
机译:分子昼夜节律调节参与负反馈回路,该回路包含负肢,PER和CRY的成分。除了时钟基因的有节奏的转录调控外,受控的亚细胞定位可能也有助于哺乳动物昼夜节律的分子机制。为了解决此问题,我们生成了带有大鼠PER2(rPER2)的转基因(TG)小鼠品系,其中大鼠PER2(rPER2)具有缺失的核定位域[NLD(-)]或完整的PER2。与野生型(WT)对照相比,过度表达NLD(-)PER2的TG小鼠的昼夜运动节律周期更长,而过度表达完整PER2的TG小鼠的昼夜运动节律周期更短。内源性PER2,CRY1和CRY2的核进入在恒定黑暗中延迟了NLD(-)PER2 TG小鼠的近视眼上核(SCN),而在完整PER2 TG小鼠的SCN中小鼠PER2(mPER2)的核进入被加速。在恒定的光照下,NLD(-)PER2 TG小鼠的运动活动变得心律不齐,而野生型动物保持节律。这些数据表明,PER2通过SCN中的核定位控制昼夜节律。此外,完整的PER2 TG小鼠的睡眠结构也受到影响,表明PER2可以调节睡眠分子机制。

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