Cells know how big they are

Abstract

In eukaryotic organisms, cell sizes are normally maintained at a stable level specific to species and cell types. However, the original sizes of two daughter cells are not always equal right after mitosis. In the Arabidopsis shoot apical meristem, besides symmetric division, asymmetric division generates a large daughter cell and a small daughter cell. If these two daughter cells go through the progression of a cell cycle within the same time course, one would expect an enhanced variability of cell sizes throughout the meristem. In fact, the cell size variability is corrected by adjusting different growth periods before the large and small daughter cell divide. How cells sense their own sizes and control the progression through cell cycles remains unclear. A recent study by D'Ario et al., 2021D'Ario M. Tavares R. Schiessl K. Desvoyes B. Gutierrez C. Howard M. Sablowski R. Cell size controlled in plants using DNA content as an internal scale.Science. 2021; 372: 1176-1181Crossref PubMed Scopus (10) Google Scholar sheds new light on this mystery. By monitoring the expression of CDT1a, whose decline indicates the G1/S transition during the cell cycle, the authors found that the CDT1a level decreases faster in the large daughter cell than in the small daughter cell. Thus, small cells after asymmetric division have a prolonged growth period before entering into DNA synthesis (S) phase. In plants, Kip-related proteins (KRPs) are involved in promoting the delayed S phase by inhibiting D-type cyclins (Zhao et al., 2012Zhao X. Harashima H. Dissmeyer N. Pusch S. Weimer A.K. Bramsiepe J. Bouyer D. Rademacher S. Nowack M.K. Novak B. et al.A general G1/S-phase cell-cycle control module in the flowering plant Arabidopsis thaliana.PLoS Genet. 2012; 8: e1002847Crossref PubMed Scopus (83) Google Scholar). D'Ario et al., 2021D'Ario M. Tavares R. Schiessl K. Desvoyes B. Gutierrez C. Howard M. Sablowski R. Cell size controlled in plants using DNA content as an internal scale.Science. 2021; 372: 1176-1181Crossref PubMed Scopus (10) Google Scholar found that, during cell division, one of these KRP proteins (KRP4) is passed on to daughter cells associated with mitotic chromosomes. As a result, KRP4 is more concentrated in small daughter cells after asymmetric division. Thus, asynchronous G1/S progression in daughter cells could be mediated by an asymmetric concentration of KRP4. The smaller cell would require a longer growth period to dilute KRP4 to a concentration that is sufficiently low to release the repression of KRP4 on G1/S transition. The next question is how the equal inheritance of KRP4 in daughter cells is achieved. The authors identified that the F-box protein FBL17, which physically interacts with KRP4 and promotes its degradation, prevents excessive KRP4 accumulation during G2 phase. Thus, only KRP4 proteins that are stabilized by association with mitotic chromosomes are transmitted to daughter cells, which provides an accurate way for cells to read DNA content as an internal ruler for cell size determination. Finally, the authors combined mathematical modeling and mutant analysis to confirm that this inhibitor dilution mechanism requires KRP4 to be precisely inherited through chromatin to robustly regulate cell size homeostasis (Figure 1). Most cellular components accumulate in proportion to cell sizes and are thus not ideal candidates to measure cell growth as internal scales (Marshall, 2016Marshall W.F. Cell geometry: how cells count and measure size.Annu. Rev. Biophys. 2016; 45: 49-64Crossref PubMed Scopus (37) Google Scholar). This study demonstrated how cells use a cell-cycle regulator as a molecular scale to read their DNA content independent of cell size. Future studies are needed to understand how this process can be precisely controlled, e.g., how KRP proteins bind chromosomes and are protected from turnover.