title: A Novel Bmal1 Mutant Mouse Reveals Essential Roles of the C-Terminal Domain on Circadian Rhythms.
abstract: 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 (Bmal1GTΔC) allele. The homozygous mutant (Bmal1GTΔC/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. Bmal1GTΔC/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 Bmal1GTΔC/GTΔC mice resulted from impaired molecular clock machinery. Expression of clock genes exhibited distinct responses to the mutant allele in Bmal1+/GTΔC and Bmal1GTΔC/GTΔC mice. Despite normal cellular localization and heterodimerization with CLOCK, overexpressed BMAL1GTΔC 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 Bmal1GTΔC mice constitute a novel model system to evaluate circadian functional mechanism of BMAL1.
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Noheon
authors.initials: N
authors.lastname: Park
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Hee-Dae
authors.initials: HD
authors.lastname: Kim
authors.affiliation: Department of Brain & Cognitive Sciences, Seoul National University, Seoul, Korea.
authors.forename: Solmi
authors.initials: S
authors.lastname: Cheon
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Hansang
authors.initials: H
authors.lastname: Row
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neuroscience & Neurodegeneration Control Research Center, Kyung Hee University, Seoul, Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Han
authors.affiliation: Department of Neuroscience & Neurodegeneration Control Research Center, Kyung Hee University, Seoul, Korea; Department of Physiology, Kyung Hee University School of Medicine, Seoul, Korea.
authors.forename: Sehyung
authors.initials: S
authors.lastname: Cho
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul, Korea; Department of Brain & Cognitive Sciences, Seoul National University, Seoul, Korea; Department of Brain Science, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu, Korea.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001683:Biological Clocks / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D015870:Gene Expression; D015151:Immunoblotting; D017403:In Situ Hybridization; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D056926:CLOCK Proteins; C538944:Clock protein, mouse