Cell-Size Control

Abstract

Cells of a given type maintain a characteristic cell size to function efficiently in their ecological or organismal context. They achieve this through the regulation of growth rates or by actively sensing size and coupling this signal to cell division. We focus this review on potential size-sensing mechanisms, including geometric, external cue, and titration mechanisms. Mechanisms that titrate proteins against DNA are of particular interest because they are consistent with the robust correlation of DNA content and cell size. We review the literature, which suggests that titration mechanisms may underlie cell-size sensing in Xenopus embryos, budding yeast, and Escherichia coli, whereas alternative mechanisms may function in fission yeast.

Figure 1.

Influence of cell size on organ and organism size. In multicellular organisms, cell size can interface with organ and organism size in one of two ways. (A) If the number of cells is fixed, changes in cell size will lead to changes in organ and, subsequently, organism size, as in C. elegans. (B) If organ size is regulated independently of cell size, changes in cell size will be compensated for by changes in cell number, resulting in a constant organ and organism size, as happens in salamanders. A mix of both mechanisms is also possible in which cell size affects organ size, but is partially compensated for by changes in cell number.

Figure 2.

The cell cycle and cell size. The cell cycle is divided into four phases. G₁ is a growth phase immediately following the previous division. S phase is when the DNA is replicated. G₂ is a second growth period followed by mitosis or M phase when the DNA is condensed and partitioned into the daughter cells. The relevant phases for cell-size control in different systems discussed in the text are as marked. MBT, midblastula transition.

Figure 3.

Cell-size measurement mechanisms. Cells can potentially sense their size via a number of different mechanisms, including (A) aspects of their cell geometry, such as surface area to volume or cell length, via intracellular gradients, (B) extracellular landmarks, and (C) titration of a constant concentration regulator, whose amount scales with cell size against a fixed “yardstick” to measure cell size.

Figure 4.

Endoreduplication increases cell size. DNA content correlates with cell size in a variety of organisms and contexts. (A) Endoreplicative cell cycles are similar to mitotic cycles without cytokinesis. Endocycling cells proceed directly from an S/G₂-like state to another G₁, whereas endomitotic cells undergo a partial mitosis but abort before cytokinesis. (B) The wing scale cells of the moth, Ephestia, vary in ploidy from 8N to 32N with higher ploidy cells being larger than lower ploidy cells (modified from data in Edgar and Orr-Weaver 2001).

Figure 5.

Midblastula transition (MBT) controlled by titration of regulators against DNA. (A) During the early cleavage cycles, Xenopus embryos divide without growth, resulting in an exponentially decreasing cell size and an exponentially increasing ratio of DNA to cytoplasm. (B) Titration of constant-concentration histones against the exponentially increasing quantity of DNA sets the timing of zygotic genome activation (ZGA) by inhibiting transcription below the threshold DNA concentration. When DNA concentration reaches a critical threshold, inhibition is relieved and transcription becomes activated (Amodeo et al. 2015). (C) Titration of key replication factors against DNA sets the timing of S-phase lengthening. When DNA concentration becomes sufficiently high, the available replication factors are no longer able to efficiently trigger S phase, resulting in a longer cell cycle (Collart et al. 2013).

Figure 6.

Proposed titration mechanisms for cell-size measurement in bacteria. (A) ATPase DnaA accumulates on origins of replication in a size-dependent manner until a critical threshold triggers replication. (B) FtsZ accumulates at the site of cytokinesis as the cell grows until reaching a threshold that triggers cytokinesis.