Circadian Clock Gene Bmal1 Is Not Essential; Functional Replacement with its Paralog, Bmal2

Feb 16, 2010Current biology : CB

The body’s main circadian gene Bmal1 is not essential and can be replaced by its similar gene Bmal2

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Abstract

Knockout of Bmal1 in mice leads to arrhythmicity and significant metabolic changes.

Most circadian clock genes in mice exist as pairs, where both genes must be knocked out to induce arrhythmicity.
Bmal1 is identified as a singularly essential clock gene, as its knockout alone causes arrhythmicity.
Knockout of Bmal1 significantly impacts longevity and metabolism.
Expression of Bmal2 can restore rhythmic locomotor activity and metabolic functions in Bmal1-knockout mice.
Bmal1 regulates Bmal2 expression, suggesting a functional redundancy between these two genes.

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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.

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Circadian Clock Gene Bmal1 Is Not Essential; Functional Replacement with its Paralog, Bmal2

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