Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
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DOI：
10.1371/journal.pone.0002762
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发表时间：
2008-07-23
期刊：
影响因子：
3.7
通讯作者：
Nave, Klaus-Armin
中科院分区：
文献类型：
--
作者：
Rossner, Moritz J.;Oster, Henrik;Wichert, Sven P.;Reinecke, Lisa;Wehr, Michael C.;Reinecke, Johannes;Eichele, Gregor;Taneja, Reshma;Nave, Klaus-Armin
昼夜节律系统提供了预测和应对日常反复挑战的基础，以维持生物体的体内平衡。人类昼夜节律反馈振荡器的不同步会导致“时差”，可能导致睡眠、精神、代谢紊乱，甚至癌症。然而，导致组织特异性时钟解体的分子机制是复杂的，并没有得到很好的理解。基于其昼夜节律表达和细胞培养实验，提出了基本的Helix-Loop-Helix （bHLH）转录因子SHARP-1（Dec2）和SHARP-2（Stra13/Dec1）作为分子钟的新型负调控因子。为了研究它们在体内的功能，我们制造了Sharp-1和Sharp-2单突变和双突变小鼠。我们的实验揭示了这两个因素在调节周期长度、生物钟基因表达的组织特异性控制和对外部信号的诱导方面的关键作用。光脉冲实验和光暗周期的快速延迟（实验时差）揭示了SHARP-1和SHARP-2在控制活性相重置动力学中的互补功能。此外，我们发现SHARP-1和sharp - 2在哺乳动物生物钟基因表达中具有双重抑制和共激活的功能。这与双突变小鼠的Per2在皮质和肝脏中的表达增加以及视交叉上核（SCN）的减少有关。在此之前，已经假设存在单独的调节夹带相位、节律幅度和周期长度的机制。Sharp-deficiency对节律性和行为再夹带的不同影响，加上组织依赖的调节功能，为进一步理解生物钟同步的复杂过程提供了新的机制基础。
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. 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. 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.
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