Numano Rika, Yamazaki Shin, Umeda Nanae, Samura Tomonori, Sujino Mitsugu, Takahashi Ri-ichi, Ueda Masatsugu, Mori Akiko, Yamada Kazunori, Sakaki Yoshiyuki, Inouye Shin-ichi T, Menaker Michael, Tei Hajime
Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3716-21. doi: 10.1073/pnas.0600060103. Epub 2006 Feb 28.
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-1alpha (EF-1alpha) or the rat neuron-specific enolase (NSE) promoter. The transgenic rats exhibited an approximately 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 Per1, 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.
已鉴定出三种哺乳动物周期（Per）基因，分别称为Per1、Per2和Per3，它们是果蝇生物钟基因period（per）的结构同源物。这三种Per基因在视交叉上核（SCN）中呈节律性表达，视交叉上核是哺乳动物的中央生物钟起搏器。SCN中这三种Per基因的mRNA水平峰值阶段略有不同。在小鼠中，光依次诱导Per1和Per2的转录本，但不诱导Per3的转录本。这些数据及其他研究表明，每种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Per1在体内生物钟系统中的功能，我们构建了两个转基因大鼠品系，其中小鼠Per1（mPer1）转录本在人延伸因子-1α（EF-1α）或大鼠神经元特异性烯醇化酶（NSE）启动子的控制下持续表达。转基因大鼠在活动和体温节律方面的昼夜周期比其野生型同胞长约0.6 - 1.0小时。转基因大鼠对光周期的同步化反应显著受损。分子分析显示，转基因大鼠的视交叉上核和眼睛中大鼠Per1（rPer1）和大鼠Per2（rPer2）mRNA的振荡幅度显著减弱。这些结果表明，过表达所提高的Per1水平或过表达动物中被抑制或消除的其节律性表达，对于行为的正常同步化和其他生物钟基因的分子振荡至关重要。
