Casein kinase 1 delta regulates the pace of the mammalian circadian clock
Department of Neurobiology; Reppert Lab; Weaver Lab; Graduate School of Biomedical Sciences, Neuroscience Program; Graduate School of Biomedical Sciences, MD/PhD Program
Animals; Base Sequence; CLOCK Proteins; Casein Kinase Idelta; Casein Kinase Iepsilon; Cell Cycle Proteins; Cells, Cultured; Circadian Rhythm; Cryptochromes; DNA Primers; Female; Fibroblasts; Flavoproteins; Half-Life; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nuclear Proteins; Period Circadian Proteins; Trans-Activators; Transcription Factors
Neuroscience and Neurobiology
Both casein kinase 1 delta (CK1delta) and epsilon (CK1epsilon) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1delta and CK1epsilon in the circadian clock mechanism, we generated mice in which the genes encoding these proteins (Csnk1d and Csnk1e, respectively) could be disrupted using the Cre-loxP system. Cre-mediated excision of the floxed exon 2 from Csnk1d led to in-frame splicing and production of a deletion mutant protein (CK1delta(Delta2)). This product is nonfunctional. Mice homozygous for the allele lacking exon 2 die in the perinatal period, so we generated mice with liver-specific disruption of CK1delta. In livers from these mice, daytime levels of nuclear PER proteins, and PER-CRY-CLOCK complexes were elevated. In vitro, the half-life of PER2 was increased by approximately 20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1delta-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1epsilon did not alter these circadian endpoints. These results reveal important functional differences between CK1delta and CK1epsilon: CK1delta plays an unexpectedly important role in maintaining the 24-h circadian cycle length.
DOI of Published Version
Mol Cell Biol. 2009 Jul;29(14):3853-66. Epub 2009 May 4. Link to article on publisher's site
Molecular and cellular biology
Etchegaray, Jean-Pierre; Machida, Kazuhiko K.; Noton, Elizabeth; Constance, Cara M.; Dallmann, Robert; Di Napoli, Marianne N.; DeBruyne, Jason P.; Lambert, Christopher M.; Yu, Elizabeth A.; Reppert, Steven M.; and Weaver, David R., "Casein kinase 1 delta regulates the pace of the mammalian circadian clock" (2009). Open Access Articles. 2180.