Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins

Neuron. 2008 Apr 10;58(1):78-88. doi: 10.1016/j.neuron.2008.01.019.

Abstract

The intrinsic period of circadian clocks is their defining adaptive property. To identify the biochemical mechanisms whereby casein kinase1 (CK1) determines circadian period in mammals, we created mouse null and tau mutants of Ck1 epsilon. Circadian period lengthened in CK1epsilon-/-, whereas CK1epsilon(tau/tau) shortened circadian period of behavior in vivo and suprachiasmatic nucleus firing rates in vitro, by accelerating PERIOD-dependent molecular feedback loops. CK1epsilon(tau/tau) also accelerated molecular oscillations in peripheral tissues, revealing its global role in circadian pacemaking. CK1epsilon(tau) acted by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Together, these whole-animal and biochemical studies explain how tau, as a gain-of-function mutation, acts at a specific circadian phase to promote degradation of PERIOD proteins and thereby accelerate the mammalian clockwork in brain and periphery.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Clocks / genetics*
  • Casein Kinase Iepsilon / antagonists & inhibitors
  • Casein Kinase Iepsilon / deficiency*
  • Casein Kinase Iepsilon / physiology
  • Cell Line
  • Cells, Cultured
  • Circadian Rhythm / genetics*
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology
  • Period Circadian Proteins
  • Phosphorylation
  • Suprachiasmatic Nucleus / physiology
  • Time Factors
  • tau Proteins / deficiency*
  • tau Proteins / metabolism*
  • tau Proteins / physiology

Substances

  • Nuclear Proteins
  • Period Circadian Proteins
  • tau Proteins
  • Casein Kinase Iepsilon