Beyond G1/S regulation: how cell size homeostasis is tightly controlled throughout the cell cycle?

Abstract

AbstractProliferating cells require control mechanisms to counteract stochastic noise and stabilize the cell mass distribution in a population. It is widely believed that size-dependent timing of the G1/S transition is the predominant control process in mammalian cells. However, a model based only on such a checkpoint cannot explain why cell lines with deficient G1/S control are still able to maintain a stable cell mass distribution or how cell mass is maintained throughout the subsequent phases of the cell cycle. To answer such questions, we used a recently developed form of Quantitative Phase Microscopy (ceQPM), which provides much-improved accuracy of individual cell mass measurement, to investigate the factors contributing to cell mass homeostasis. We find that cell mass homeostasis is robustly maintained, despite disruptions of the normal G1/S transition or cell growth rate. The coefficient of variation in mass, nevertheless declines well after the G1/S transition and throughout the cell cycle in both transformed and non-transformed cells. Furthermore, the cell growth rate responds to cell mass in different ways in different cell types. Growth rate modulation is conveyed by mTORC1-dependent and mTORC1-independent processes, which are independently regulated. Slightly reduced mass accumulation, below exponential growth can effectively reduce cell mass variation in a population. Both size-dependent cell cycle regulation and size-dependent growth rate modulation contribute to cell mass homeostasis. Together they form a compensatory network that strictly controls the coefficient of variation of cell mass in a population. These findings opens new avenues for the discovery of underlying molecular mechanisms. Furthermore, understanding feedback directly on cell growth may provide insights into fundamental principles of cell size control in normal proliferating and terminally differentiated cells, as well as cells in pathological circumstances.