Constitutive expression of thePeriod1gene impairs behavioral and molecular circadian rhythms

• DOI: 10.1073/pnas.0600060103
• Publication Date: 2006-03-01T02:48:37Z
• Authors: Rika Numano; Shin Yamazaki; Nanae Umeda; Tomonori Samura; Mitsugu Sujino; Ri-ichi Takahashi; Masatsugu Ueda; Akiko Mori; Kazunori Yamada; Yoshiyuki Sakaki; Shin-Ichi T. Inouye; Michael Menaker; Hajime Tei
• Keywords: Male; 0303 health sciences; Base Sequence; Behavior, Animal; Gene Expression; Nuclear Proteins; Cell Cycle Proteins; Period Circadian Proteins; Eye; Circadian Rhythm; Rats; Animals, Genetically Modified; Mice; 03 medical and health sciences; Animals; Female; Suprachiasmatic Nucleus; RNA, Messenger; Rats, Wistar; Transcription Factors

Three mammalianPeriod(Per) genes, termedPer1,Per2, andPer3, have been identified as structural homologues of theDrosophilacircadian clock gene,period(per). The threePergenes are rhythmically expressed in the suprachiasmatic nucleus (SCN), the central circadian pacemaker in mammals. The phases of peak mRNA levels for the threePergenes in the SCN are slightly different. Light sequentially induces the transcripts ofPer1andPer2but not ofPer3in mice. These data and others suggest that eachPergene has a different but partially redundant function in mammals. To elucidate the function ofPer1in the circadian systemin vivo, we generated two transgenic rat lines in which the mousePer1(mPer1) transcript was constitutively expressed under the control of either the human elongation factor-1α (EF-1α) or the rat neuron-specific enolase (NSE) promoter. The transgenic rats exhibited an ≈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 ratPer1(rPer1) and ratPer2(rPer2) mRNAs were significantly attenuated in the SCN and eyes of the transgenic rats. These results indicate that either the level ofPer1, 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.