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Science 314 (5803): 1304-1308

Copyright © 2006 by the American Association for the Advancement of Science

Dissecting the Functions of the Mammalian Clock Protein BMAL1 by Tissue-Specific Rescue in Mice

Erin L. McDearmon,1,2 Kush N. Patel,2 Caroline H. Ko,2,3 Jacqueline A. Walisser,4 Andrew C. Schook,1,2 Jason L. Chong,2 Lisa D. Wilsbacher,2 Eun J. Song,1,2 Hee-Kyung Hong,1,2 Christopher A. Bradfield,4 Joseph S. Takahashi1,2*

Abstract: The basic helix-loop-helix (bHLH)–Per-Arnt-Sim (PAS) domain transcription factor BMAL1 is an essential component of the mammalian circadian pacemaker. Bmal1–/– mice lose circadian rhythmicity but also display tendon calcification and decreased activity, body weight, and longevity. To investigate whether these diverse functions of BMAL1 are tissue-specific, we produced transgenic mice that constitutively express Bmal1 in brain or muscle and examined the effects of rescued gene expression in Bmal1–/– mice. Circadian rhythms of wheel-running activity were restored in brain-rescued Bmal1–/– mice in a conditional manner; however, activity levels and body weight were lower than those of wild-type mice. In contrast, muscle-rescued Bmal1–/– mice exhibited normal activity levels and body weight yet remained behaviorally arrhythmic. Thus, Bmal1 has distinct tissue-specific functions that regulate integrative physiology.

1 Howard Hughes Medical Institute, Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA.
2 Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA.
3 Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
4 McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53706, USA.

* To whom correspondence should be addressed. E-mail: j-takahashi{at}northwestern.edu


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