TY - JOUR
T1 - Circadian Clock Gene Bmal1 Is Not Essential; Functional Replacement with its Paralog, Bmal2
AU - Shi, Shuqun
AU - Hida, Akiko
AU - McGuinness, Owen P.
AU - Wasserman, David H.
AU - Yamazaki, Shin
AU - Johnson, Carl Hirschie
N1 - Funding Information:
We are grateful to many individuals for their assistance and/or supplying of materials for this project. In particular, we are grateful to H. Tei and K. Hanaoka for their gift of the hEF1a promoter construct, to H. Yan for the anti-myc antibody, to C. Bradfield for the B1ko mouse, to J. Takahashi for the PER2::LUC mouse, to N. Cermakian for the pCS2-mBmal1/2 plasmids, to R. Emeson for the SV40 intron, to Q.-Y. Zhou for the PK2.8-luc reporter, to D. Nelson for the mNpas2 construct, and to C. Weitz and S. Reppert for the plasmids encoding mCry1, mCry2, and mClock. We also thank R. Emeson and the Vanderbilt Transgenic Mouse and Embryonic Stem Cell Shared Resource for their unfailingly generous assistance and advice in the construction of the B2Tg mouse. Finally, we thank A. Schoenhard for assistance and suggestions and Y. Xu and B. Robertson for help with figure preparation. This work was supported by grants from the National Institutes of Health (R01-MH43836, R21-NS054991, and K02-MH01179 to C.H.J., R01-NS051278 to S.Y., and U24 DK59637 to the Vanderbilt Mouse Metabolic Phenotyping Center) and a Pilot and Feasibility grant from the Vanderbilt Diabetes and Research Training Center (2P60DK020593).
PY - 2010/2/23
Y1 - 2010/2/23
N2 - Most of the central circadian clock genes in the mouse exist as paralog pairs (Per1 and Per2, Cry1 and Cry2, Clock and Npas2) in which each gene of the pair must be knocked out to confer arrhythmicity [1-3]. The only exception to this pattern is Bmal1 (also known as Mop3), the single knockout of which confers arrhythmicity, despite the presence of its paralog, Bmal2 (also known as Mop9) [4]. The knockout of Bmal1 also has significant effects on longevity, metabolism, etc. [5, 6]. These results have led to the conclusion that Bmal1 is a singularly essential clock gene and that Bmal2 has a minimal role in the clock system. In contrast, we find that expression of Bmal2 from a constitutively expressed promoter can rescue the clock and metabolic phenotypes of Bmal1-knockout mice, including rhythmic locomotor activity, rhythmic metabolism, low body weight, and enhanced fat deposition. Combined with the data of Bunger and colleagues, who reported that knockout of Bmal1 downregulates Bmal2 [4], we conclude that Bmal1 and Bmal2 form a circadian paralog pair that is functionally redundant and that, in the mouse, Bmal2 is regulated by Bmal1 such that knockout of Bmal1 alone results in a functionally double Bmal1 and Bmal2 knockout. Therefore, the role(s) of Bmal2 may be more important than has been appreciated heretofore.
AB - Most of the central circadian clock genes in the mouse exist as paralog pairs (Per1 and Per2, Cry1 and Cry2, Clock and Npas2) in which each gene of the pair must be knocked out to confer arrhythmicity [1-3]. The only exception to this pattern is Bmal1 (also known as Mop3), the single knockout of which confers arrhythmicity, despite the presence of its paralog, Bmal2 (also known as Mop9) [4]. The knockout of Bmal1 also has significant effects on longevity, metabolism, etc. [5, 6]. These results have led to the conclusion that Bmal1 is a singularly essential clock gene and that Bmal2 has a minimal role in the clock system. In contrast, we find that expression of Bmal2 from a constitutively expressed promoter can rescue the clock and metabolic phenotypes of Bmal1-knockout mice, including rhythmic locomotor activity, rhythmic metabolism, low body weight, and enhanced fat deposition. Combined with the data of Bunger and colleagues, who reported that knockout of Bmal1 downregulates Bmal2 [4], we conclude that Bmal1 and Bmal2 form a circadian paralog pair that is functionally redundant and that, in the mouse, Bmal2 is regulated by Bmal1 such that knockout of Bmal1 alone results in a functionally double Bmal1 and Bmal2 knockout. Therefore, the role(s) of Bmal2 may be more important than has been appreciated heretofore.
KW - MOLNEURO
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U2 - 10.1016/j.cub.2009.12.034
DO - 10.1016/j.cub.2009.12.034
M3 - Article
C2 - 20153195
AN - SCOPUS:76749168029
SN - 0960-9822
VL - 20
SP - 316
EP - 321
JO - Current Biology
JF - Current Biology
IS - 4
ER -