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


RESULTS
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
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.
Rossner
Moritz J
MJ
Max-Planck-Institute of Experimental Medicine, Göttingen, Germany. rossner@em.mpg.de
Oster
Henrik
H
Wichert
Sven P
SP
Reinecke
Lisa
L
Wehr
Michael C
MC
Reinecke
Johannes
J
Eichele
Gregor
G
Taneja
Reshma
R
Nave
Klaus-Armin
KA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D053595:Embryonic Stem Cells / Q000166:cytology; D005786:Gene Expression Regulation; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009991:Oscillometry; D056950:Period Circadian Proteins; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C470968:Bhlhb3 protein, mouse; C485778:Hey2 protein, mouse; C513312:Per2 protein, mouse