title: Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock.
abstract: 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.
authors.affiliation: Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Pukou District, Nanjing 210061, China.
authors.forename: Guangsen
authors.initials: G
authors.lastname: Shi
authors.forename: Lijuan
authors.initials: L
authors.lastname: Xing
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Qu
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Moli
authors.initials: M
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptácek
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D015694:Gene Products, rev / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020218:Response Elements / Q000502:physiology; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D044783:F-Box Proteins; C519794:Fbxl3 protein, mouse; D015694:Gene Products, rev; D037021:Thyroid Hormone Receptors alpha