Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms

doi:10.1073/pnas.0600060103

Constitutive expression of the Period1 gene impairs behavioral and molecular circadian rhythms

*Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
^§Department of Biology, University of Virginia, Charlottesville, VA 22903-2477;
^‖Department of Physics, Informatics, and Biology, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan;
**Y. S. New Technology Institute, Inc., 1198-4 Utsunomiyashi, Iwaso-machi, Tochigi 321-0973, Japan;
^††Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan; and
^‡‡RIKEN Genomic Sciences Center, Human Genome Research Group, W402, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan

Communicated by Joseph S. Takahashi, Northwestern University, Evanston, IL, January 4, 2006
↵ ^†R.N., S.Y., and N.U. contributed equally to this work. (received for review March 25, 2005)

Abstract

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.

Footnotes

^§§To whom correspondence should be sent at the present address:
Research Group of Chronogenomics, Mitsubishi Kagaku Institute of Life Sciences, 11, Minami-Oya, Mahida, Tokyo 194-8511, Japan.
E-mail: tei{at}libra.ls.m-kagaku.co.jp
↵ ^‡Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200.
↵ ^¶Present address: Department of Biological Sciences, Vanderbilt University, VU Station B, Box 35-1634, Nashville, TN 37235-1634.
Author contributions: H.T. designed research; R.N., S.Y., N.U., T.S., M.S., R.-i.T., M.U., A.M., K.Y., and H.T. performed research; R.N., Y.S., and H.T. contributed new reagents/analytic tools; R.N., S.Y., N.U., T.S., M.S., Y.S., S.-I.T.I., M.M., and H.T. analyzed data; and R.N., S.Y., S.-I.T.I., M.M., and H.T. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

SCN,

suprachiasmatic nucleus;

NSE,

neuron-specific enolase;

EF-1α,

elongation factor-1α;

CT,

circadian time;

LD,

light/dark;

DD,

constant darkness.