Tissue-Specific Functions of the Mammalian Clock Protein BMAL1

Christopher A. Bradfield, Ph.D.
University of Wisconsin, Madison
R37ES0057003

NIEHS grantee Christopher Bradfield has shown that expression of a clock gene known as BMAL1 in specific tissues is necessary for proper physiological function. Using mutant mice, Bradfield and colleagues determined that circadian rhythmicity was normalized only when the protein is produced in the brain, but normal activity and body weight required expression in muscle tissue. These findings are consistent with the tissue-specific variation in circadian gene expression and suggest that central circadian clock components act differently in a variety of tissues. They further suggest that tissue-specific regulation of clock gene expression could be a valuable tool in determining the regulation of circadian rhythms in mammals at the molecular, cellular and systems levels.

Clock genes control circadian rhythms in mammals and contribute to other aspects of normal physiology, behavior, and health. BMAL1 is one such gene and its inactivation in mice causes disturbances in circadian rhythms and alterations in activity levels, body weight, and physiologic function.

Research into dioxin toxicology and the Ah receptor-ARNT signal transduction pathway led to the discovery of the family of proteins that BMAL1 is a part of – the PAS proteins. They act as both sensors of environmental cues and transmitters of these signals to the nuclei of cells. The recent explosion in the number of known members of the PAS family led to the discovery of sensors that are involved in responses to low atmospheric oxygen, tissue hypoxia, exposure to polycyclic aromatic pollutants, and body rhythms.

Bradfield has been instrumental in the discovery of PAS proteins and the Ah receptor signaling pathway. The grant that supports this work was initially awarded as a FIRST award—an award designed especially for young investigators. Through his high productivity and exceptional grant writing skills, his grant was converted to a prestigious Method to Extend Research In Time (MERIT) award.

Citation: McDearmon EL, Patel KN, Ko CH, Walisser JA, Schook AC, Chong JL, Wilsbacher LD, Song EJ, Hong HK, Bradfield CA, Takahashi JS. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science. 2006 Nov 24;314(5803):1304-8.