Charvin G, Cross F R, Siggia E D
Laboratory of Yeast Molecular Genetics and Center for Studies in Physics and Biology, The Rockefeller University, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6632-7. doi: 10.1073/pnas.0809227106. Epub 2009 Apr 3.
Phase-locking (frequency entrainment) of an oscillator, in which a periodic extrinsic signal drives oscillations at a frequency different from the unperturbed frequency, is a useful property for study of oscillator stability and structure. The cell cycle is frequently described as a biochemical oscillator; however, because this oscillator is tied to key biological events such as DNA replication and segregation, and to cell growth (cell mass increase), it is unclear whether phase locking is possible for the cell cycle oscillator. We found that forced periodic expression of the G(1) cyclin CLN2 phase locks the cell cycle of budding yeast over a range of extrinsic periods in an exponentially growing monolayer culture. We characterize the behavior of cells in a pedigree using a return map to determine the efficiency of entrainment to the externally controlled pulse. We quantify differences between mothers and daughters and how synchronization of an expanding population differs from synchronization of a single oscillator. Mothers only lock intermittently whereas daughters lock completely and in a different period range than mothers. We can explain quantitative features of phase locking in both cell types with an analytically solvable model based on cell size control and how mass is partitioned between mother and daughter cells. A key prediction of this model is that size control can occur not only in G(1), but also later in the cell cycle under the appropriate conditions; this prediction is confirmed in our experimental data. Our results provide quantitative insight into how cell size is integrated with the cell cycle oscillator.
振荡器的锁相（频率同步）是一种研究振荡器稳定性和结构的有用特性，其中周期性的外部信号以不同于未受干扰频率的频率驱动振荡。细胞周期常被描述为一种生化振荡器；然而，由于这种振荡器与DNA复制和分离等关键生物学事件以及细胞生长（细胞质量增加）相关联，目前尚不清楚细胞周期振荡器是否能够实现锁相。我们发现，在指数生长的单层培养物中，G1期细胞周期蛋白CLN2的强制周期性表达可在一系列外部周期范围内使芽殖酵母的细胞周期实现锁相。我们使用返回映射来表征谱系中细胞的行为，以确定对外部控制脉冲的同步效率。我们量化了母细胞和子细胞之间的差异，以及不断扩大的群体的同步与单个振荡器的同步有何不同。母细胞只是间歇性地锁相，而子细胞则完全锁相，且锁相周期范围与母细胞不同。我们可以用一个基于细胞大小控制以及质量如何在母细胞和子细胞之间分配的可解析模型来解释两种细胞类型中锁相的定量特征。该模型的一个关键预测是，大小控制不仅可以发生在G1期，在适当条件下也可以发生在细胞周期的后期；我们的实验数据证实了这一预测。我们的结果为细胞大小如何与细胞周期振荡器整合提供了定量的见解。
