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Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice
Moritz J Rossner1, Henrik Oster, Sven P Wichert
1Max-Planck-Institute of Experimental Medicine, Göttingen, Germany. rossner@em.mpg.de
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.
Insights
SHARP-1 and SHARP-2 transcription factors are crucial for maintaining circadian rhythm stability. Their absence disrupts clock gene expression and impairs the body's ability to adjust to environmental cues like jet lag.
Area of Science:
- Chronobiology
- Molecular Biology
- Genetics
Background:
- The circadian system regulates homeostasis and anticipates daily environmental changes.
- Circadian disruption is linked to various health issues, including sleep, metabolic, and psychiatric disorders.
- Molecular mechanisms underlying tissue-specific clock desynchronization remain incompletely understood.
Purpose of the Study:
- To investigate the in vivo function of basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1 and SHARP-2 in regulating the molecular clock.
- To elucidate the roles of SHARP-1 and SHARP-2 in controlling circadian period length, gene expression, and entrainment to external cues.
- To explore the complementary functions of SHARP-1 and SHARP-2 in activity phase resetting kinetics during experimental jet lag.
Main Methods:
- Generation of Sharp-1 and Sharp-2 single and double mutant mice.
- Analysis of circadian expression patterns and cell culture experiments.
- Light-pulse experiments and rapid delays of the light-dark cycle to simulate jet lag.
Main Results:
- SHARP-1 and SHARP-2 play critical roles in regulating circadian period length and tissue-specific clock gene expression.
- These factors exhibit complementary functions in controlling activity phase resetting kinetics following simulated jet lag.
- SHARP-1 and SHARP-2 function as context-dependent repressors and co-activators of mammalian clock gene expression, impacting Per2 expression amplitudes differently across brain regions and tissues.
Conclusions:
- The study provides new mechanistic insights into the complex processes of circadian clock synchronization.
- Differential effects of SHARP deficiency on rhythmicity and re-entrainment highlight distinct regulatory mechanisms for phase, amplitude, and period.
- Tissue-dependent regulatory functions of SHARP-1 and SHARP-2 offer a basis for understanding clock synchronization disruptions.
