Cell size sensing in animal cells coordinates anabolic growth rates with cell cycle progression to maintain uniformity of cell size

Abstract

The uniformity of cell size in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether growth rates of individual cells 6Monitoring nuclear growth in live cells confirmed that these decreases in variance reflect a process that selectively inhibits the growth of large cells while accelerating growth of small cells. 8We also detected cell-size-dependent adjustments of G1 length, which further reduce variability.Combining our assays with chemical and genetic perturbations confirmed that cells employ two 10 strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size.Introduction:

Mycobacteria Modify Their Cell Size Control under Sub-Optimal Carbon Sources

“…This is coupled with the observation that growth rate is dependent on birth length (Figure 2D), with smaller cells growing faster than larger cells at birth (for cells grown in glycerol but not for cells grown in acetate or pyruvate; Figures 5B, 6B); a dependence that is not observed in E. coli . How these correlations affect the properties of cell size control is not clear and should be the subject of further modeling studies (Modi et al, 2016), though we note that the striking negative dependence of growth rate on birth length has recently been observed in mammalian cells (Ginzberg et al, 2017). …”

Bistable switches as integrators and actuators during cell cycle progression

“…The Rb-E2F switch is also influenced by cell size and other metabolic measures of a cell's readiness to divide. Although the precise mechanism through which cell size regulates G1 progression in mammalian cells remains unclear [61], an inhibitor-dilution mechanism has recently been proposed to control cell cycle re-entry in yeast [62,63]. During G1, expression of the yeast G1 cyclin Cln3 scales proportionally with cell size, while the expression of Whi5, a transcriptional inhibitor of cell cycle progression, remains constant.…”

Computationally Enhanced Quantitative Phase Microscopy Reveals Autonomous Oscillations in Mammalian Cell Growth

“…Growth rate control in cells has long been postulated to be caused by size-dependent control of the cell cycle particularly control of the G1/S transition (1)(2)(3). Recently, there has been evidence supporting the notion that the size-dependent regulation of growth rate could play an important role in maintaining size homeostasis in proliferating cells (4)(5)(6)(7)(8). Because the growth rate of individual cells is much more difficult to measure than the timing of events in the cell cycle, such as cell division or DNA replication, there is as currently not much quantitative evidence as to how much growth rate adjustments contribute to size homeostasis and where in the cell cycle these corrections might occur.…”

“…These limitations are restrictive when we attempt to resolve the dependence of growth on size throughout the cell cycle. There are other simpler measurements based on correlations, such as the use of the nuclear area (5) or assaying a constitutively expressed fluorescent protein (16), as proxies for cell mass. However, these proxies are probably not quantitative enough to make useful growth rate measurements, since the correlations between the proxies and cell mass are noisy, rendering growth rate measurements very challenging.…”