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Casein kinase 1 delta regulates the pace of the mammalian circadian clock

Jean-Pierre Etchegaray1, Kazuhiko K Machida, Elizabeth Noton

  • 1Department of Neurobiology, LRB-723, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.

Molecular and Cellular Biology
|May 6, 2009
PubMed

Insights

Casein kinase 1 delta (CK1delta) is crucial for maintaining the 24-hour circadian cycle length in mammals. Disruption of CK1delta in mice led to longer circadian rhythms, unlike CK1epsilon.

Area of Science:

  • Molecular Biology
  • Chronobiology

Background:

  • Core clock proteins in the mammalian circadian oscillator are phosphorylated by casein kinase 1 delta (CK1delta) and epsilon (CK1epsilon).
  • Understanding the specific roles of CK1delta and CK1epsilon in circadian rhythm regulation is essential.

Purpose of the Study:

  • To investigate the distinct roles of CK1delta and CK1epsilon in the mammalian circadian clock mechanism.
  • To determine the impact of CK1delta and CK1epsilon gene disruption on circadian rhythms.

Main Methods:

  • Generated mice with disruptions in Csnk1d (encoding CK1delta) and Csnk1e (encoding CK1epsilon) genes using the Cre-loxP system.
  • Created liver-specific CK1delta disruption in mice due to perinatal lethality of homozygous mutants.
  • Analyzed PER protein and PER-CRY-CLOCK complex levels, PER2 protein half-life, and PER2::luciferase bioluminescence rhythms in vitro and in vivo.

Main Results:

  • Liver-specific CK1delta disruption resulted in elevated daytime nuclear PER proteins and PER-CRY-CLOCK complexes.
  • In vitro studies showed a ~20% increase in PER2 half-life and a 2-hour lengthening of PER2::luciferase bioluminescence rhythms.
  • CK1delta-deficient fibroblast cultures exhibited prolonged circadian rhythms, while CK1epsilon disruption had no significant effect on these circadian endpoints.

Conclusions:

  • CK1delta plays a critical, previously underestimated role in maintaining the precise 24-hour length of the mammalian circadian cycle.
  • Significant functional divergence exists between CK1delta and CK1epsilon in their contributions to circadian clock regulation.

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