Leloup J C, Goldbeter A
Unité de Chronobiologie Théorique des Sciences, Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, Brussels, Belgium.
J Biol Rhythms. 1998 Feb;13(1):70-87. doi: 10.1177/074873098128999934.
The authors present a model for circadian oscillations of the Period (PER) and Timeless (TIM) proteins in Drosophila. The model for the circadian clock is based on multiple phosphorylation of PER and TIM and on the negative feedback exerted by a nuclear PER-TIM complex on the transcription of the per and tim genes. Periodic behavior occurs in a large domain of parameter space in the form of limit cycle oscillations. These sustained oscillations occur in conditions corresponding to continuous darkness or to entrainment by light-dark cycles and are in good agreement with experimental observations on the temporal variations of PER and TIM and of per and tim mRNAs. Birhythmicity (coexistence of two periodic regimes) and aperiodic oscillations (chaos) occur in a restricted range of parameter values. The results are compared to the predictions of a model based on the sole regulation by PER. Both the formation of a complex between PER and TIM and protein phosphorylation are found to favor oscillatory behavior. Determining how the period depends on several key parameters allows us to test possible molecular explanations proposed for the altered period in the per(l) and per(s) mutants. The extended model further allows the construction of phase-response curves based on the light-induced triggering of TIM degradation. These curves, established as a function of both the duration and magnitude of the effect of a light pulse, match the phase-response curves obtained experimentally in the wild type and per(s) mutant of Drosophila.
作者提出了果蝇中周期蛋白（PER）和无时间蛋白（TIM）昼夜节律振荡的模型。生物钟模型基于PER和TIM的多重磷酸化以及核PER-TIM复合物对per和tim基因转录施加的负反馈。周期性行为以极限环振荡的形式出现在参数空间的一个大区域中。这些持续振荡发生在对应于持续黑暗或由明暗周期诱导的条件下，并且与关于PER和TIM以及per和tim mRNA时间变化的实验观察结果高度一致。双节律性（两种周期性状态的共存）和非周期性振荡（混沌）出现在参数值的受限范围内。将结果与基于仅由PER调节的模型的预测进行比较。发现PER和TIM之间复合物的形成以及蛋白质磷酸化都有利于振荡行为。确定周期如何依赖于几个关键参数使我们能够测试为per(l)和per(s)突变体中改变的周期提出的可能分子解释。扩展模型进一步允许基于光诱导的TIM降解触发构建相位响应曲线。这些曲线作为光脉冲效应的持续时间和幅度的函数建立，与在果蝇野生型和per(s)突变体中实验获得的相位响应曲线相匹配。
