Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock

Both casein kinase 1 delta (CK1 delta) and epsilon (CK1 epsilon) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1 delta and CK1 epsilon 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 (CK1 delta(Delta 2)). 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 CK1 delta. 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 similar to 20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1 delta-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1 epsilon did not alter these circadian end-points. These results reveal important functional differences between CK1 delta and CK1 epsilon: CK1 delta plays an unexpectedly important role in maintaining the 24-h circadian cycle length.