The Mechanics of Mitotic Cell Rounding

Abstract

When animal cells enter mitosis, they round up to become spherical. This shape change is accompanied by changes in mechanical properties. Multiple studies using different measurement methods have revealed that cell surface tension, intracellular pressure and cortical stiffness increase upon entry into mitosis. These cell-scale, biophysical changes are driven by alterations in the composition and architecture of the contractile acto-myosin cortex together with osmotic swelling and enable a mitotic cell to exert force against the environment. When the ability of cells to round is limited, for example by physical confinement, cells suffer severe defects in spindle assembly and cell division. The requirement to push against the environment to create space for spindle formation is especially important for cells dividing in tissues. Here we summarize the evidence and the tools used to show that cells exert rounding forces in mitosis in vitro and in vivo, review the molecular basis for this force generation and discuss its function for ensuring successful cell division in single cells and for cells dividing in normal or diseased tissues.

Keywords: Ect2; actin cortex; cell mechanics; ezrin; mitosis; mitotic rounding; myosin; osmotic pressure.

FIGURE 1

Techniques that have been applied to measure mitotic cell mechanics. For detailed description of methods (see Box 1).

FIGURE 2

The molecular basis of mitotic force generation. The transition from interphase (left) to mitosis (center) in a single adherent cell in tissue culture is accompanied by loss of substrate adhesion, an increase in acto-myosin cortical tension and an increase in intracellular pressure due to water influx. The box shows the molecular changes that control cortical tension. Activation of Ect2 by Cdk1 phosphorylation and nuclear export leads to the activation of RhoA, which leads to the assembly of actin filaments (red) and myosin II mini-filaments (blue) at the cell cortex. The rigid, contractile acto-myosin cortex is attached to the plasma membrane by ERM proteins (orange), activated in mitosis through phosphorylation by the kinase, Slik. A network of intermediate filament protein, vimentin (purple), underlies the cortical actin network, which also contributes to cortical tension.

FIGURE 3

Mitotic rounding in tissues and tumoroids. Examples of mitotic cells rounding while surrounded by other cells (A) in a non-transformed confluent epithelial cell monolayer (MCF10A) plated on a soft polyacrylamide hydrogel, stained with phalloidin-TRITC to visualize actin (cyan) and DAPI to visualize DNA (Gray) (Image by HM), (B) in vivo in a mitotic sensory organ precursor cell (labeled with LifeAct-GFP in cyan) in the notum of the developing Drosophila pupa. The whole tissue is labeled with tubulin (gray) to stain the mitotic spindle. (Image by Nelio Rodrigues) and (C) frozen section of an MCF-7 tumor spheroid grown for 14 days within a PEG/heparin hydrogel in 3D, stained with phalloidin-TRITC (cyan)/DAPI(gray) for F-actin/nuclei (image by AT). Scale bars are 10 μm.