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The mammalian circadian clock is an endogenous biological timer comprised of transcriptional/translational feedback loops of clock genes.  Bmal1  encodes an indispensable transcription factor for the generation of circadian rhythms. Here, we report a new circadian mutant mouse from gene-trapped embryonic stem cells harboring a C-terminus truncated  Bmal1  ( Bmal1    GTΔC  ) allele. The homozygous mutant ( Bmal1    GTΔC/GTΔC  ) mice immediately lost circadian behavioral rhythms under constant darkness. The heterozygous ( Bmal1    +/GTΔC  ) mice displayed a gradual loss of rhythms, in contrast to  Bmal1    +/-   mice where rhythms were sustained.  Bmal1    GTΔC/GTΔC   mice also showed arrhythmic mRNA and protein expression in the SCN and liver. Lack of circadian reporter oscillation was also observed in cultured fibroblast cells, indicating that the arrhythmicity of  Bmal1    GTΔC/GTΔC   mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in  Bmal1    +/GTΔC   and  Bmal1    GTΔC/GTΔC   mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1 GTΔC  was unable to activate transcription of  Per1  promoter and BMAL1-dependent CLOCK degradation. These results indicate that the C-terminal region of  Bmal1  has pivotal roles in the regulation of circadian rhythms and the  Bmal1    GTΔC   mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1.

A Novel Bmal1 Mutant Mouse Reveals Essential Roles of the C-Terminal Domain on Circadian Rhythms