Reassessment of the basis of cell size control based on analysis of cell-to-cell variability

ABSTRACT Fundamental mechanisms governing cell size control and homeostasis are still poorly understood. The relationship between sizes at division and birth in single cells is used as a metric to categorize the basis of size homeostasis [1–3]. Cells dividing at a fixed size regardless of birth size (sizer) are expected to show a division-birth slope of 0, whereas cells dividing after growing for a fixed size increment (adder) have an expected slope of +1 [4]. These two theoretical values are, however, rarely experimentally observed. Here we investigate possible reasons for this discrepancy. Rod-shaped fission yeast Schizosaccharomyces pombe cells divide at a fixed surface area [5, 6], and exhibit a division-birth slope of 0.23±0.04, significantly different from the sizer value of zero. To understand whether fission yeast uses a mix of sizer and adder control, or whether size sensing is simply imprecise, we developed a mathematical model of sizer control, including the relevant sources of variation. Our results support pure sizer control and show that deviation from zero slope is exaggerated by measurement of an inappropriate geometrical quantity (e.g., length instead of area), combined with cell-to-cell radius variability. The model predicts that mutants with greater errors in size sensing or septum positioning paradoxically appear to behave as better sizers. Furthermore, accounting for cell width variability, we show that pure sizer control can in some circumstances reproduce the apparent adder behaviour observed in E. coli . These findings demonstrate that refined analysis of geometric variation can lead to new insights into cell size control.