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Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2
Shuqun Shi1, Akiko Hida, Owen P McGuinness
1Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
Abstract:
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.
Insights
Brain and muscle ARNT-like 1 (Bmal1) and its paralog Bmal2 are functionally redundant circadian clock genes. Bmal1 knockout mice show rescued phenotypes when Bmal2 is expressed, suggesting Bmal2
Area of Science:
- Circadian biology
- Molecular genetics
- Mammalian physiology
Background:
- Most central circadian clock genes in mice exist as paralog pairs.
- Bmal1 (Brain and muscle ARNT-like 1) is considered essential, as its single knockout causes arrhythmicity.
- Bmal2 was previously thought to have a minimal role in the circadian clock system.
Purpose of the Study:
- To investigate the functional redundancy and regulatory relationship between Bmal1 and Bmal2.
- To determine if Bmal2 plays a more significant role in circadian rhythmicity and metabolism than previously understood.
Main Methods:
- Constitutive expression of Bmal2 in Bmal1-knockout mice.
- Assessment of circadian locomotor activity and metabolic parameters.
- Analysis of gene expression data from previous studies.
Main Results:
- Constitutive expression of Bmal2 rescued the arrhythmicity and metabolic phenotypes in Bmal1-knockout mice.
- Rescued phenotypes included restored rhythmic locomotor activity, normalized metabolism, reduced body weight, and mitigated fat deposition.
- Previous findings indicate Bmal1 knockout downregulates Bmal2 expression.
Conclusions:
- Bmal1 and Bmal2 function as a redundant circadian paralog pair.
- Bmal2's role is more significant than previously appreciated.
- Bmal1 regulates Bmal2 expression, implying a Bmal1 knockout effectively creates a double knockout of both genes.
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