The mammalian circadian clock is composed of interlocking feedback loops. 
Cryptochrome is a central component in the core negative feedback loop, whereas 
Rev-Erbα, a member of the nuclear receptor family, is an essential component of 
the interlocking loop. To understand the roles of different clock genes, we 
conducted a genetic interaction screen by generating single- and double-mutant 
mice. We found that the deletion of Rev-erbα in F-box/leucine rich-repeat 
protein (Fbxl3)-deficient mice rescued its long-circadian period phenotype, and 
our results further revealed that FBXL3 regulates Rev-Erb/retinoic acid 
receptor-related orphan receptor-binding element (RRE)-mediated transcription by 
inactivating the Rev-Erbα:histone deacetylase 3 corepressor complex. By 
analyzing the Fbxl3 and Cryptochrome 1 double-mutant mice, we found that FBXL3 
also regulates the amplitudes of E-box-driven gene expression. These two 
separate roles of FBXL3 in circadian feedback loops provide a mechanism that 
contributes to the period determination and robustness of the clock.