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

Both casein kinase 1 delta (CK1δ) and epsilon (CK1ɛ) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1δ and CK1ɛ 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 (CK1δΔ2). 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 CK1δ. 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 ∼20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1δ-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1ɛ did not alter these circadian endpoints. These results reveal important functional differences between CK1δ and CK1ɛ: CK1δ plays an unexpectedly important role in maintaining the 24-h circadian cycle length