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

Abstract

Summary Most of the central circadian clock genes in the mouse exist as paralog pairs (Per1/Per2, Cry1/Cry2, Clock/Npas2) that must both be knocked out to confer arhythmicity [1, 2, 3]. The only exception to this pattern is Bmal1/Mop3, the single knockout of which confers arhythmicity despite the presence of its paralog Bmal2/Mop9 [4]. The knockout of Bmal1 also has significant effects on longevity, metabolism, et al. [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 coworkers who reported that knockout of Bmal1 down-regulates Bmal2 [4], we conclude that Bmal1 and Bmal2 form a circadian paralog pair that is functionally redundant, but that in the mouse, Bmal2 is regulated by Bmal1 such that knockout of Bmal1 alone results in a functionally double Bmal1/Bmal2 knockout. Therefore, the role(s) of Bmal2 may be more important than has been appreciated heretofore.

Bmal1in the Nervous System Is Essential for Normal Adaptation of Circadian Locomotor Activity and Food Intake to Periodic Feeding

“…FAA in N-Bmal1 Ϫ/ Ϫ mice, as well as feeding-entrained rhythms of Per1 and Per2 mRNA in their brain, might be driven by residual cells in the nervous system having nonrecombined functional Bmal1 fl alleles (i.e., somatic mosaicism), by Bmal2 (a paralog of Bmal1) (Shi et al, 2010), and/or by Bmal1 outside the nervous system. Circadian mechanisms without canonical clock machinery may be also involved (Hastings et al, 2008).…”

The daily rhythm of mice

“…This particular finding suggested that peripheral oscillators are directly involved in the control of rhythmic physiological processes (see below). In Mop3/Bmal1 knock out mice, the expression of the related Bmal2 gene was drastically down regulated [17,21]. A transgenic rescue of Bmal2 expression in Mop3/Bmal1 knock out mice restored rhythmic locomotor activity and the other phenotypes as well.…”

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

“…Intriguingly, the core clock proteins CLOCK, CRY, and PER all have homologs that serve a backup function, and although the BMAL1-null mouse is highly arrhythmic, it has been reported that BMAL2 expression is abolished by BMAL1 ablation, but overexpression of BMAL2 can compensate for loss of BMAL1 (Shi et al 2010). Accordingly, for all clock components, loss of only one homolog has relatively minor effects, while depletion of all subtypes causes severe circadian phenotypes (van der Horst et al 1999;Bae et al 2001;DeBruyne et al 2007;Shi et al 2010), similar to what we found for the Rev-erbs. Taken together, our data thus suggest that the relationship between Rev-erba and Rev-erbb is more reminiscent of that of core clock proteins, where a backup system exists for every component, in contrast to most other NR subtype families.…”