TY - JOUR
T1 - Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms
AU - Numano, Rika
AU - Yamazaki, Shin
AU - Umeda, Nanae
AU - Samura, Tomonori
AU - Sujino, Mitsugu
AU - Takahashi, Ri Ichi
AU - Ueda, Masatsugu
AU - Mori, Akiko
AU - Yamada, Kazunori
AU - Sakaki, Yoshiyuki
AU - Inouye, Shin Ichi T
AU - Menaker, Michael
AU - Tei, Hajime
PY - 2006/3/7
Y1 - 2006/3/7
N2 - 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-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 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.
AB - 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-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 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.
KW - Entrainment
KW - Transgenic rats
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U2 - 10.1073/pnas.0600060103
DO - 10.1073/pnas.0600060103
M3 - Article
C2 - 16537451
AN - SCOPUS:33644863308
SN - 0027-8424
VL - 103
SP - 3716
EP - 3721
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -