Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2.
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. 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). The knockout of Bmal1 also has significant effects on longevity, metabolism, etc. 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, 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.
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
Shuqun
S
Shi
Akiko
A
Hida
Owen P
OP
McGuinness
David H
DH
Wasserman
Shin
S
Yamazaki
Carl Hirschie
CH
Johnson
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D015151:Immunoblotting; D008124:Locomotion / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C431792:Arntl2 protein, mouse; D056925:Circadian Rhythm Signaling Peptides and Proteins