Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice

PLoS One. 2008 Jul 23;3(7):e2762. doi: 10.1371/journal.pone.0002762.


Background: The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood.

Methodology/principal findings: Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1(Dec2) and SHARP-2(Stra13/Dec1) were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag) unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN) of double mutant mice.

Conclusions/significance: The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Circadian Rhythm
  • Embryonic Stem Cells / cytology
  • Gene Expression Regulation*
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Models, Genetic
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oscillometry
  • Period Circadian Proteins
  • Phenotype
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*


  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhb3 protein, mouse
  • Cell Cycle Proteins
  • Hey2 protein, mouse
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Repressor Proteins
  • Transcription Factors