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

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Science  24 Nov 2006:
Vol. 314, Issue 5803, pp. 1304-1308
DOI: 10.1126/science.1132430

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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.

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