Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms
Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms
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DOI：
10.1073/pnas.0600060103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Tei, H
中科院分区：
文献类型：
--
作者：
Numano, R;Yamazaki, S;Tei, H
三个哺乳动物周期（Per）基因，命名为Per 1，Per 2和Per 3，已被确定为果蝇昼夜节律钟基因周期（Per）的结构同源物。这三个Per基因在哺乳动物的中枢昼夜节律起搏器视交叉上核（SCN）中有节律地表达。SCN中三个Per基因的峰值mRNA水平的阶段略有不同。在小鼠中，光依次诱导Per 1和Per 2的转录，但不诱导Per 3的转录。这些数据和其他数据表明，每个Per基因在哺乳动物中具有不同但部分冗余的功能。为了阐明Per 1在体内昼夜节律系统中的功能，我们产生了两个转基因大鼠品系，其中小鼠Per 1（mPer 1）转录本在人延伸因子-1 α（EF-1 α）或大鼠神经元特异性烯醇化酶（NSE）启动子的控制下组成型表达。转基因大鼠表现出约0.6-1.0小时的昼夜节律周期比野生型同胞在活动和体温节律。在转基因大鼠中，响应于光周期的夹带显著受损。分子分析显示，大鼠Per 1（rPer 1）和大鼠Per 2（rPer 2）mRNA的振荡幅度在转基因大鼠的SCN和眼睛中显著减弱。这些结果表明，无论是由过表达提高的Peri水平，还是在过表达动物中被抑制或消除的其节律性表达，对于其他时钟基因的行为和分子振荡的正常夹带都是至关重要的。
Three mammalian Period (Per) genes, termed Per1, Per2, and Per3, have been identified as structural homologues of the Drosophila circadian clock gene, period (per). The three Per genes are rhythmically expressed in the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. The phases of peak mRNA levels for the three Per genes in the SCN are slightly different. Light sequentially induces the transcripts of Per1 and Per2 but not of Per3 in mice. These data and others suggest that each Per gene has a different but partially redundant function in mammals. To elucidate the function of Per1 in the circadian system in vivo, we generated two transgenic rat lines in which the mouse Per1 (mPer1) transcript was constitutively expressed under the control of either the human elongation factor-1 alpha (EF-1 alpha) or the rat neuron-specific enolase (NSE) promoter. The transgenic rats exhibited an approximate to 0.6-1.0-h longer circadian period than their wild-type siblings in both activity and body temperature rhythms. Entrainment in response to light cycles was dramatically impaired in the transgenic rats. Molecular analysis revealed that the amplitudes of oscillation in the rat Per1 (rPer1) and rat Per2 (rPer2) mRNAs were significantly attenuated in the SCN and eyes of the transgenic rats. These results indicate that either the level of Peri, which is raised by overexpression, or its rhythmic expression, which is damped or abolished in over expressing animals, is critical for normal entrainment of behavior and molecular oscillation of other clock genes.