Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice

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.