Scheper T O, Klinkenberg D, van Pelt J, Pennartz C
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, The Netherlands.
J Biol Rhythms. 1999 Jun;14(3):213-20. doi: 10.1177/074873099129000623.
A fundamental question in the field of circadian rhythms concerns the biochemical and molecular nature of the oscillator. There is strong evidence that circadian oscillators are cell autonomous and rely on periodic gene expression. In Drosophila, Neurospora, Aplysia, and vertebrates, circadian oscillators are thought to be based on molecular autoregulatory loops composed of transcription, translation, and negative feedback by proteins on nuclear transcription. By studying a mathematical model of molecular clocks based on this general concept, the authors sought to determine which features such clocks must have to generate robust and stable oscillations and to allow entrainment by external stimuli such as light. The model produced circadian oscillations as an emergent property even though a time delay in protein synthesis and rate constants of the feedback loop were much shorter than 24 h. Along with the delay in protein production, strong nonlinear interactions in macromolecular synthesis and nuclear feedback appeared to be required for the model to show well-behaved oscillatory behavior. Realistic phase-shifting patterns induced by external stimuli could be achieved by multiple mechanisms-namely, up- and downward perturbations of protein or mRNA synthesis or degradation rates. The model makes testable predictions about interactions between clock elements and mechanisms of entrainment and may help to understand the functions of the intricate molecular interactions governing circadian rhythmogenesis.
昼夜节律领域的一个基本问题涉及振荡器的生化和分子本质。有充分证据表明，昼夜振荡器是细胞自主的，且依赖于周期性的基因表达。在果蝇、脉孢菌、海兔和脊椎动物中，昼夜振荡器被认为是基于由转录、翻译以及蛋白质对核转录的负反馈所组成的分子自动调节环。通过研究基于这一普遍概念的分子钟数学模型，作者试图确定此类时钟必须具备哪些特征才能产生稳健且稳定的振荡，并能被诸如光等外部刺激所调节。即便蛋白质合成的时间延迟以及反馈环的速率常数远短于24小时，该模型仍产生了作为一种涌现特性的昼夜振荡。除了蛋白质产生的延迟外，大分子合成和核反馈中强烈的非线性相互作用似乎也是该模型展现良好振荡行为所必需的。外部刺激所诱导的现实的相位移动模式可通过多种机制来实现，即蛋白质或mRNA合成或降解速率的向上和向下扰动。该模型对时钟元件之间的相互作用以及调节机制做出了可检验的预测，可能有助于理解控制昼夜节律发生的复杂分子相互作用的功能。
