On the Molecular Mechanisms Regulating Animal Cell Size Homeostasis

Abstract

Cell size is fundamental to cell physiology because it sets the scale of intracellular geometry, organelles, and biosynthetic processes. In animal cells, size homeostasis is controlled through two phenomenologically distinct mechanisms. First, size-dependent cell cycle progression ensures that smaller cells delay cell cycle progression to accumulate more biomass than larger cells prior to cell division. Second, size-dependent cell growth ensures that larger and smaller cells grow slower per unit mass than more optimally sized cells. This decade has seen dramatic progress in single-cell technologies establishing the diverse phenomena of cell size control in animal cells. Here, we review this recent progress and suggest pathways forward to determine the underlying molecular mechanisms.

Keywords: G1/S stochastic sizer; cell cycle; cell growth rate; cell size; protein dilution.

Figure 1.. Balance of cell growth and division determines cell size homeostasis.

A. Cell size-dependent cell cycle progression: smaller cells spend more time in certain phases of the cell cycle and grow more than larger cells. B. Cell size-dependent growth rate adjustment: smaller cells accumulate biomass faster than larger cells. C. Cell size homeostasis is achieved through both cell size-dependent growth rate adjustment and cell size-dependent cell cycle progression. D. Cells closer to the optimal size are more efficient and grow more rapidly than smaller or larger cells.

Figure 2.. Phenomenological models of cell-size-dependent cell cycle progression.

A. Adder model: all cells, small and large, add the same amount of mass through the cell cycle. Consequently, cell size converges to the target value over a few generations. The target value is equal to the increment by which the cells grow through a cell cycle. B. Sizer model: all cells, small and large, divide (or complete a certain phase of the cell cycle) when they reach the same target size. The target cell size is achieved within one generation. C. Stochastic G1/S sizer: larger cells have a higher rate of G1/S progression than smaller cells. This process is probabilistic, as opposed to a deterministic sizer where G1/S passage is determined by a fixed cell size threshold. D. Mammalian cells demonstrate a stochastic G1 sizer and stochastic S/G2/M timer. G1 duration is variable but it is negatively correlated with the cell size at birth, while S/G2/M duration is more size-independent.

Figure 3.. Scaling and non-scaling expression of regulatory proteins.

A. The amount of a scaling protein in the cell is proportional to cell size, while the amount of a non-scaling protein does not increase in proportion to cell size. B. Concentration of scaling proteins remains constant across different sizes, while non-scaling proteins are diluted by cell growth.

Figure 4 Key Figure.. Molecular mechanisms of mammalian G1/S sizer.

A. Inhibitor dilution model: activators of cell cycle progression scale with cell size so that their concentration does not change, while an inhibitor such as RB does not scale and is diluted by cell growth. B. Dilution of a G1/S cell cycle inhibitor protein RB leads to an increase in the rate cells progress through the G1/S transition. Shades of grey on the inset illustrate changes in the nuclear RB concentration. C. Inhibitor dilution, combined with molecular noise and cell-to-cell variability results is a stochastic sizer: on average, the cells born larger have a shorter G1 phase and grow less than the cells born smaller. D. Two proposed molecular mechanisms for cell-size-dependent G1/S progression: RB dilution by cell growth and size-dependent p38 kinase activation. In RB dilution model, cell growth dilutes the cell cycle inhibitor RB. This leads to the increased G1/S progression rate. In p38 model, small cell size activates the p38 MAP kinase, which inhibits G1/S. Thus, in both mechanisms larger cells pass through G1/S and divide sooner than smaller cells.