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Dissecting the Functions of the Mammalian Clock Protein BMAL1 by Tissue-Specific Rescue in Mice
Erin L. McDearmon,1,2Kush N. Patel,2Caroline H. Ko,2,3Jacqueline A. Walisser,4Andrew C. Schook,1,2Jason L. Chong,2Lisa D. Wilsbacher,2Eun J. Song,1,2Hee-Kyung Hong,1,2Christopher A. Bradfield,4Joseph S. Takahashi1,2*
The basic helix-loop-helix (bHLH)–Per-Arnt-Sim (PAS) domaintranscription factor BMAL1 is an essential component of themammalian circadian pacemaker. Bmal1–/– mice losecircadian rhythmicity but also display tendon calcificationand decreased activity, body weight, and longevity. To investigatewhether these diverse functions of BMAL1 are tissue-specific,we produced transgenic mice that constitutively express Bmal1in brain or muscle and examined the effects of rescued geneexpression in Bmal1–/– mice. Circadian rhythms ofwheel-running activity were restored in brain-rescued Bmal1–/–mice in a conditional manner; however, activity levels and bodyweight were lower than those of wild-type mice. In contrast,muscle-rescued Bmal1–/– mice exhibited normal activitylevels and body weight yet remained behaviorally arrhythmic.Thus, Bmal1 has distinct tissue-specific functions that regulateintegrative 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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[DOI: 10.1126/stke.3632006tw404] |Abstract »
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