The Nuclear-to-Cytoplasmic Ratio: Coupling DNA Content to Cell Size, Cell Cycle, and Biosynthetic Capacity

Abstract

Though cell size varies between different cells and across species, the nuclear-to-cytoplasmic (N/C) ratio is largely maintained across species and within cell types. A cell maintains a relatively constant N/C ratio by coupling DNA content, nuclear size, and cell size. We explore how cells couple cell division and growth to DNA content. In some cases, cells use DNA as a molecular yardstick to control the availability of cell cycle regulators. In other cases, DNA sets a limit for biosynthetic capacity. Developmentally programmed variations in the N/C ratio for a given cell type suggest that a specific N/C ratio is required to respond to given physiological demands. Recent observations connecting decreased N/C ratios with cellular senescence indicate that maintaining the proper N/C ratio is essential for proper cellular functioning. Together, these findings suggest a causative, not simply correlative, role for the N/C ratio in regulating cell growth and cell cycle progression.

Keywords: DNA-to-cytoplasmic ratio; biosynthetic activity; cell cycle; cell size; nuclear-to-cytoplasmic ratio; polyploidy.

Figure 1

Altered cell cycles can change cellular DNA content. A typical mitotic cell cycle consists of two growth phases (G1 and G2) punctuated by DNA synthesis (S) and mitosis (M). Specific cyclins and cyclin-dependent kinases facilitate transitions between the cell cycle phases. Diverse altered cell cycle modes operate in different tissues. Polytene salivary gland cells of Drosophila larva endocycle between S and G phases, resulting in increased ploidy and cell size. The sister chromatids are held in close proximity. Endocycling Arabidopsis thaliana leaf cells cycle between the G and S phases, but the chromatin is dispersed. In some cell types, including tobacco hawk moth (Manduca) wing scales, the cells show truncated mitosis that includes prophase (p) and metaphase (m) but abort during anaphase (a), thereby omitting telophase (t) and cytokinesis (c). Ashbya gossypii undergoes karyokinesis during telophase but omits cytokinesis, resulting in multinucleate cells. Multinucleated cells also occur in mammalian muscle through cell fusions. In asynthetic cell fission observed in zebrafish skin cells, cell division occurs without S phase to rapidly increase the cell number but reduce DNA content.

Figure 2

Macromolecule concentrations respond differently to increasing cell size. (a) The production of some proteins increases in proportion to growth, resulting in constant concentration over a range of cell sizes (scaling; green). Other proteins fail to keep pace with cell growth or are actively degraded in large cells, resulting in reduced concentration with cell growth (subscaling; blue). Finally, some proteins increase faster than the average growth rate or are stabilized in large cells and therefore increase in concentration at larger cell sizes (superscaling; red). (b) Scaling proteins (green) double in amount as volume doubles, resulting in a slope of ~1. Subscaling (blue) can be the result of production that does not keep pace with total growth or degradation in large cells. One important class of subscaling proteins are those that are held at a constant amount (such as histones within a cell cycle phase) rather than at constant concentrations. Superscaling proteins increase in amount faster than total growth, resulting in a slope >1.

Figure 3

Examples of DNA as a yardstick to measure cell size. (a) Arabidopsis meristem cells produce the S phase inhibitor KRP4 in G1 phase and partition an equal amount into each daughter cell regardless of cell size. Equal partitioning is ensured through association with DNA, which uncouples the amount of KRP4 that each daughter cell receives from the volume of cytoplasm. In G2 phase, KRP4 disassociates from the chromatin, and its concentration is diluted by cell growth. When KRP4 concentration falls below a set concentration, it triggers cell cycle progression. Therefore, small daughter cells spend more time growing in G1 phase compared to large daughter cells (32). A similar mechanism has been proposed for Rb in mammals (178). (b) During pre-midblastula transition embryonic reductive divisions, the cell volume reduces with every cycle. Here, total embryo-wide histone concentration is approximately constant but becomes increasingly incorporated into DNA as the number of nuclei increases. The increasing number of nuclei results in a decrease in the histone concentration in individual nuclei. In Drosophila, histone H3 acts as a competitive inhibitor of the cell cycle inhibitor, Chk1. The reduction in H3 nuclear concentrations results in activation of Chk1 to ensure cell cycle slowing at the correct N/C ratio (146).