Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
Math Biosci. 2024 Nov;377:109291. doi: 10.1016/j.mbs.2024.109291. Epub 2024 Sep 4.
The cell division cycle is a fundamental physiological process displaying a great degree of plasticity during the course of multicellular development. This plasticity is evident in the transition from rapid and stringently-timed divisions of the early embryo to subsequent size-controlled mitotic cycles. Later in development, cells may pause and restart proliferation in response to myriads of internal or external signals, or permanently exit the cell cycle following terminal differentiation or senescence. Beyond this, cells can undergo modified cell division variants, such as endoreplication, which increases their ploidy, or meiosis, which reduces their ploidy. This wealth of behaviours has led to numerous conceptual analogies intended as frameworks for understanding the proliferative program. Here, we aim to unify these mechanisms under one dynamical paradigm. To this end, we take a control theoretical approach to frame the cell cycle as a pair of arrestable and mutually-inhibiting, doubly amplified, negative feedback oscillators controlling chromosome replication and segregation events, respectively. Under appropriate conditions, this framework can reproduce fixed-period oscillations, checkpoint arrests of variable duration, and endocycles. Subsequently, we use phase plane and bifurcation analysis to explain the dynamical basis of these properties. Then, using a physiologically realistic, biochemical model, we show that the very same regulatory structure underpins the diverse functions of the cell cycle control network. We conclude that Newton's cradle may be a suitable mechanical analogy of how the cell cycle is regulated.
细胞分裂周期是一个基本的生理过程，在多细胞发育过程中表现出很大的可塑性。这种可塑性表现在从早期胚胎的快速和严格定时分裂到随后的大小控制有丝分裂周期的转变。在发育后期，细胞可能会根据无数内部或外部信号暂停并重新开始增殖，或者在终端分化或衰老后永久退出细胞周期。除此之外，细胞还可以经历经过修饰的细胞分裂变体，例如增加其倍性的内复制，或减少其倍性的减数分裂。这种丰富的行为导致了许多旨在作为理解增殖程序的框架的概念类比。在这里，我们旨在将这些机制统一在一个动力学范例下。为此，我们采用控制理论方法将细胞周期表示为一对可停止和相互抑制的、双重放大的负反馈振荡器，分别控制染色体复制和分离事件。在适当的条件下，该框架可以再现固定周期的振荡、具有可变持续时间的检查点停滞以及内周期。随后，我们使用相平面和分岔分析来解释这些特性的动力学基础。然后，使用生理上现实的生化模型，我们表明细胞周期控制网络的不同功能都基于相同的调节结构。我们得出结论，牛顿摆可能是细胞周期如何被调节的一个合适的机械类比。
