Cell-size maintenance: universal strategy revealed

Abstract

How cells maintain a stable size has fascinated scientists since the beginning of modern biology, but has remained largely mysterious. Recently, however, the ability to analyze single bacteria in real time has provided new, important quantitative insights into this long-standing question in cell biology. In nature, cells can be as small as ∼0.2 mm (e.g., Mycoplasma gallicepticum) and as large as ∼0.1 m (e.g., Syringammina fragilissima), spanning almost six orders of magnitude. Individual organisms, however, show much narrower size distributions, and under constant conditions most single-celled microorganisms change their size by only two-fold between birth and division. For Escherichia coli, the variance of size distribution at division is ∼10% of the average [1], a strong indication that these cells know how to maintain stable size. KeywordsIn 1958, Schaechter, Maaløe, and Kjeldgaard established a general underlying principle in microbial physiology known as the 'growth law' [2]. It states that the average cell size is exponentially proportional to the average nutrient-imposed growth rate. That is, if we culture the cells in an unknown liquid medium X, we just need to measure the growth curve and we can predict the exact average size of the cells in that medium. What determines the cell size, and how do cells maintain their size under a given growth condition?Historically, cell size homeostasis has been discussed in the context of two major paradigms: sizer, in which the cell actively monitors its size and triggers the cell cycle once it reaches a critical size, and timer, in which the cell attempts to grow for a specific amount of time before division. Pinning down which model is correct poses daunting experimental challenges, because size control study requires quantitative measurements at the single-cell level with extreme precision [3] and throughput [4] under tightly controlled experimental conditions. It has only been in the past few years that the data with sufficient quantity and quality [4,5] have become available to address size maintenance in the way researchers since the 1950s dreamed of.The latest in the series of single-cell studies is the collaborative work by the Scherer and Dinner groups [5]. They studied Caulobacter crescentus, a model bacterial organism known for asymmetric cell division and cellular differentiation. Upon division, the two daughter cells of C. crescentus are distinct from each other in shape and size: the larger 'stalked' cell binds to a surface, whereas the smaller 'swarmer' cell is initially motile and differentiates into a stalked cell. This allowed the authors long-term continuous observations of growth and division of the stalked cells in a flow chamber, producing amounts of single-cell data comparable to previous work in E. coli [4]. The authors addressed two questions: (i) How do cell size and generation time change with respect to the temperature-imposed growth rate? (ii) What is the relationship between the size at birth and division?The answer to the first q...

Noise-driven growth rate gain in clonal cellular populations

“…Indeed, cell size at birth and generation time are weakly correlated negatively (Pearson correlation coefficient, −0.48 ∼ −0.22; SI Appendix, Fig. S12), and this effect must be considered to account for cell size stability (3,(31)(32)(33)(34)(35). Nevertheless, our results suggest that, as far as age-related parameters and population growth rates are concerned, cell size information does not play a predominant role in E. coli over a broad set of culture conditions.…”

Characterization of dependencies between growth and division in budding yeast

“…An important distinction between the current study and previous analyses is the measurement of cell size. In our datasets, cell size was measured via a fluorescent protein-based proxy for cell mass, whereas recent work in bacteria and budding yeast has focused on cell volume [6,[11][12][13]. Elements of cell volume in budding yeast, particularly the vacuoles, are known to undergo dynamic, regulated changes over the course of the cell cycle [39].…”

“…Assuming a consistent single-cell growth rate across cells, these tenets are sufficient to maintain a consistent size distribution in the population. Recent studies in bacteria have revealed an alternative size control model by which cells add a relatively constant amount of volume over the cell cycle, regardless of their birth size [11][12][13]. Here we use time-lapse microscopy datasets tracking characteristics of individual cells to test these models and further characterize coordination between growth and division in budding yeast.…”

Cell-Size Homeostasis and the Incremental Rule in a Bacterial Pathogen

“…How this cell-size homeostasis is achieved remains a topic of intense research (6)(7)(8)(9)(10)(11)(12)(13). Recent studies in bacteria propose that rod-shaped bacteria such as Escherichia coli and Bacillus subtilis follow an incremental rule (also known as the ''adder'') (6,7,11,12,14), whereby each cell adds a constant volume to their cell body before dividing. New studies take advantage of technical advancements in microfluidics and live-cell imaging to follow thousands of cell divisions.…”

“…Rod-shaped bacteria have fairly constant cell width, which means that cell length may be used as a proxy for size. The increment in cell length before division is independent of cell's length at birth, ruling out alternative size-regulation rules such as the ''timer'', according to which cells would divide at regular intervals, and the ''sizer'', where cells would divide when reaching a maximum size (7,11,12). In a timer model, any noise in the regulatory mechanism would lead to fluctuations in the time of division (Dt), causing the distribution of cell sizes to spread out over consecutive divisions; but that is not the case here.…”