Cited 2 time in webofscience Cited 2 time in scopus

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

Title
A Novel Bmal1 Mutant Mouse Reveals Essential Roles of the C-Terminal Domain on Circadian Rhythms
Authors
Park, N[Park, Noheon]Kim, HD[Kim, Hee-Dae]Cheon, S[Cheon, Solmi]Row, H[Row, Hansang]Lee, J[Lee, Jiyeon]Han, DH[Han, Dong-Hee]Cho, S[Cho, Sehyung]Kim, K[Kim, Kyungjin]
DGIST Authors
Kim, K[Kim, Kyungjin]
Issue Date
2015-09-22
Citation
PLoS ONE, 10(9)
Type
Article
Article Type
Article
Keywords
Animal CellAnimal ExperimentAnimal TissueBMAL1 GeneCarboxy Terminal SequenceCircadian RhythmControlled StudyDarknessDimerizationEmbryoEmbryonic Stem CellFemaleFibroblast CultureGene ExpressionHeterozygoteHomozygoteLiverMaleMessenger RNAMolecular ClockMouseMutantNon-HumanPER1 GenePER1 ProteinPromoter RegionProtein DegradationProtein DomainProtein ExpressionProtein LocalizationReporter GeneSuprachiasmatic NucleusTranscription Factor ARNTLTranscription Factor ClockTranscription Initiation
ISSN
1932-6203
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. © 2015 Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI
http://hdl.handle.net/20.500.11750/2587
DOI
10.1371/journal.pone.0138661
Publisher
Public Library of Science
Files:
There are no files associated with this item.
Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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