Journal Article

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

D'Souza, Heather, Chang, Nancy, Patel, Nish, Ginzberg, Miriam Bracha, Kafri, Ran, Kirschner, Marc W

2018

Overview

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell’s target size. Animal cells come in many different sizes. In humans, for example, egg cells are thousands of times larger than sperm cells. Yet cells of any given type are often strikingly similar in size. The cells that line the surface of organs including the skin and kidneys are especially uniform; in fact a loss of size uniformity in certain tumors is a sign of malignancy. What kind of regulation could enable separate cells within a tissue to have the same size? One possibility is that each type of cell is programmed with a specific target size, and that a cell can sense if it strays from its target and take steps to compensate. Animal cells sensing their own size was first reported in the 1960s, and now Ginzberg et al. confirm that human cells grown in the laboratory do indeed monitor their size and correct deviations from their target. It turns out that two separate and independent processes help to keep all the cells in the population roughly uniform in size. Firstly, proliferating human cells that are smaller than their target size spend longer growing before they divide. Secondly, at two time points between cell divisions, large cells adjust their growth rate such that they grow slower than small cells. To show these processes in action, Ginzberg et al. introduced mutations or chemicals that perturbed the length of time between cell divisions or the rate of a cell’s growth. As expected, most of these perturbations had only a modest influence on cell size, due to the cell’s compensatory strategies. Cells that had less time to grow compensated by more quickly making new protein molecules, meaning that they still had enough material to build two new cells by the time they had to divide. In contrast, if a cell’s division was artificially delayed, it reduced its growth rate to stop it from becoming too large. Similarly, cells grown in conditions that slow the production of proteins extended the time between their cell divisions to give them enough time to accumulate the material required for two new cells. In a recent related study, Liu, Ginzberg et al. identified some of the molecules that a human cell uses to sense its own size. Together these two studies now pave the road to answering a fundamental question in cell biology: what is the elusive cell size sensor? Understanding how cells sense their size will open a window onto how quantitative information is programmed, sensed and communicated within living cells. These findings will shed also new light onto how cells specialize into cell types of different sizes, and what happens when cells lose the ability to sense or regulate their size in diseases like cancers.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Cell Biology / Cell cycle / Cell Cycle - drug effects / Cell Cycle - physiology / cell cycle regulation / Cell division / Cell Division - drug effects / Cell Division - physiology / Cell growth / Cell Line / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Proliferation - physiology / Cell Size / cell size control / Cells (Biology) / Computational and Systems Biology / Cyclin-dependent kinase 4 / Cyclin-Dependent Kinase 4 - metabolism / Cytological research / Data analysis / Growth / Growth factors / Growth rate / growth rate regulation / HeLa Cells / Homeostasis / Humans / mammalian cells / Metabolism / Microscopy, Fluorescence / Physiological aspects / Proteins / Signal Transduction - physiology / Skin / Sperm / Time-Lapse Imaging - methods / Tumors / Xenobiotics - classification / Xenobiotics - pharmacology / Yeast