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.
McDearmon
Erin L
EL
Howard Hughes Medical Institute, Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA.
Patel
Kush N
KN
Ko
Caroline H
CH
Walisser
Jacqueline A
JA
Schook
Andrew C
AC
Chong
Jason L
JL
Wilsbacher
Lisa D
LD
Song
Eun J
EJ
Hong
Hee-Kyung
HK
Bradfield
Christopher A
CA
Takahashi
Joseph S
JS
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D002114:Calcinosis; D018797:Cell Cycle Proteins / Q000235:genetics; D022202:Chromosomes, Artificial, Bacterial; D002940:Circadian Rhythm; D015870:Gene Expression; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D009928:Organ Specificity; D056950:Period Circadian Proteins; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D013710:Tendons / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse