Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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}

Circadian Rhythms in Cell Maturation.
B. C. Du Pre, T. A. B. Van Veen, M. E. Young, M. A. Vos, P. A. Doevendans, and L. W. Van Laake (2014)
Physiology 29, 72-83
   Abstract »    Full Text »    PDF »
Brain and muscle Arnt-like 1 is a key regulator of myogenesis.
S. Chatterjee, D. Nam, B. Guo, J. M. Kim, G. E. Winnier, J. Lee, R. Berdeaux, V. K. Yechoor, and K. Ma (2013)
J. Cell Sci. 126, 2213-2224
   Abstract »    Full Text »    PDF »
Clock Genes Influence Gene Expression in Growth Plate and Endochondral Ossification in Mice.
T. Takarada, A. Kodama, S. Hotta, M. Mieda, S. Shimba, E. Hinoi, and Y. Yoneda (2012)
J. Biol. Chem. 287, 36081-36095
   Abstract »    Full Text »    PDF »
Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex.
N. Huang, Y. Chelliah, Y. Shan, C. A. Taylor, S.-H. Yoo, C. Partch, C. B. Green, H. Zhang, and J. S. Takahashi (2012)
Science 337, 189-194
   Abstract »    Full Text »    PDF »
Assessment of circadian rhythms in humans: comparison of real-time fibroblast reporter imaging with plasma melatonin.
S. Hasan, N. Santhi, A. S. Lazar, A. Slak, J. Lo, M. von Schantz, S. N. Archer, J. D. Johnston, and D.-J. Dijk (2012)
FASEB J 26, 2414-2423
   Abstract »    Full Text »    PDF »
Contribution of FSH and triiodothyronine to the development of circadian clocks during granulosa cell maturation.
G. Chu, I. Misawa, H. Chen, N. Yamauchi, Y. Shigeyoshi, S. Hashimoto, and M.-a. Hattori (2012)
Am J Physiol Endocrinol Metab 302, E645-E653
   Abstract »    Full Text »    PDF »
Genetic Interaction of Per1 and Dec1/2 in the Regulation of Circadian Locomotor Activity.
B. Bode, A. Shahmoradi, M. J. Rossner, and H. Oster (2011)
J Biol Rhythms 26, 530-540
   Abstract »    PDF »
Bmal1 in the Nervous System Is Essential for Normal Adaptation of Circadian Locomotor Activity and Food Intake to Periodic Feeding.
M. Mieda and T. Sakurai (2011)
J. Neurosci. 31, 15391-15396
   Abstract »    Full Text »    PDF »
Tissue-intrinsic dysfunction of circadian clock confers transplant arteriosclerosis.
B. Cheng, C. B. Anea, L. Yao, F. Chen, V. Patel, A. Merloiu, P. Pati, R. W. Caldwell, D. J. Fulton, and R. D. Rudic (2011)
PNAS 108, 17147-17152
   Abstract »    Full Text »    PDF »
Synaptotagmin10-Cre, a Driver to Disrupt Clock Genes in the SCN.
J. Husse, X. Zhou, A. Shostak, H. Oster, and G. Eichele (2011)
J Biol Rhythms 26, 379-389
   Abstract »    PDF »
Effects of Vasoactive Intestinal Peptide Genotype on Circadian Gene Expression in the Suprachiasmatic Nucleus and Peripheral Organs.
D. H. Loh, J. M. Dragich, T. Kudo, A. M. Schroeder, T. J. Nakamura, J. A. Waschek, G. D. Block, and C. S. Colwell (2011)
J Biol Rhythms 26, 200-209
   Abstract »    PDF »
Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms.
Y. Lee, R. Chen, H.-m. Lee, and C. Lee (2011)
J. Biol. Chem. 286, 7033-7042
   Abstract »    Full Text »    PDF »
Reproductive biology of female Bmal1 null mice.
M. J. Boden, T. J. Varcoe, A. Voultsios, and D. J. Kennaway (2010)
Reproduction 139, 1077-1090
   Abstract »    Full Text »    PDF »
SirT1 in muscle physiology and disease: lessons from mouse models.
M. Vinciguerra, M. Fulco, A. Ladurner, V. Sartorelli, and N. Rosenthal (2010)
Dis. Model. Mech. 3, 298-303
   Abstract »    Full Text »    PDF »
Interaction of MAGED1 with nuclear receptors affects circadian clock function.
X. Wang, J. Tang, L. Xing, G. Shi, H. Ruan, X. Gu, Z. Liu, X. Wu, X. Gao, and Y. Xu (2010)
EMBO J. 29, 1389-1400
   Abstract »    Full Text »    PDF »
Rev-erb-{alpha}: an integrator of circadian rhythms and metabolism.
H. Duez and B. Staels (2009)
J Appl Physiol 107, 1972-1980
   Abstract »    Full Text »    PDF »
Clock genes and metabolic disease.
B. Marcheva, K. M. Ramsey, A. Affinati, and J. Bass (2009)
J Appl Physiol 107, 1638-1646
   Abstract »    Full Text »    PDF »
Time Is of the Essence: Vascular Implications of the Circadian Clock.
R. D. Rudic (2009)
Circulation 120, 1714-1721
   Full Text »    PDF »
AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation.
K. A. Lamia, U. M. Sachdeva, L. DiTacchio, E. C. Williams, J. G. Alvarez, D. F. Egan, D. S. Vasquez, H. Juguilon, S. Panda, R. J. Shaw, et al. (2009)
Science 326, 437-440
   Abstract »    Full Text »    PDF »
Pressed for time: the circadian clock and hypertension.
R. D. Rudic and D. J. Fulton (2009)
J Appl Physiol 107, 1328-1338
   Abstract »    Full Text »    PDF »
Ryanodine Receptors Are Regulated by the Circadian Clock and Implicated in Gating Photic Entrainment.
K. L. Gamble and C. M. Ciarleglio (2009)
J. Neurosci. 29, 11717-11719
   Full Text »    PDF »
Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production.
G. H. Son, S. Chung, H. K. Choe, H.-D. Kim, S.-M. Baik, H. Lee, H.-W. Lee, S. Choi, W. Sun, H. Kim, et al. (2008)
PNAS 105, 20970-20975
   Abstract »    Full Text »    PDF »
Response to Comment on "Differential Rescue of Light- and Food-Entrainable Circadian Rhythms".
P. M. Fuller, J. Lu, and C. B. Saper (2008)
Science 322, 675b
   Abstract »    Full Text »    PDF »
Physiological significance of a peripheral tissue circadian clock.
K. A. Lamia, K.-F. Storch, and C. J. Weitz (2008)
PNAS 105, 15172-15177
   Abstract »    Full Text »    PDF »
Differential Rescue of Light- and Food-Entrainable Circadian Rhythms.
P. M. Fuller, J. Lu, and C. B. Saper (2008)
Science 320, 1074-1077
   Abstract »    Full Text »    PDF »
Disruption of Clock Gene Expression Alters Responses of the Aryl Hydrocarbon Receptor Signaling Pathway in the Mouse Mammary Gland.
X. Qu, R. P. Metz, W. W. Porter, V. M. Cassone, and D. J. Earnest (2007)
Mol. Pharmacol. 72, 1349-1358
   Abstract »    Full Text »    PDF »
An Aryl Hydrocarbon Receptor Odyssey to the Shores of Toxicology: The Deichmann Lecture, International Congress of Toxicology-XI.
A. B. Okey (2007)
Toxicol. Sci. 98, 5-38
   Abstract »    Full Text »    PDF »
The Multiple Facets of Per2.
U. Albrecht, A. Bordon, I. Schmutz, and J. Ripperger (2007)
Cold Spring Harb Symp Quant Biol 72, 95-104
   Abstract »    PDF »
Physiological Importance of a Circadian Clock Outside the Suprachiasmatic Nucleus.
K.-F. Storch, C. Paz, J. Signorovitch, E. Raviola, B. Pawlyk, T. Li, and C. J. Weitz (2007)
Cold Spring Harb Symp Quant Biol 72, 307-318
   Abstract »    PDF »
Suprachiasmatic Nucleus Clock Time in the Mammalian Circadian System.
H. Okamura (2007)
Cold Spring Harb Symp Quant Biol 72, 551-556
   Abstract »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882