A mechanosensory system controls cell shape changes during mitosis

Abstract

Essential life processes are heavily controlled by a variety of positive and negative feedback systems. Cytokinesis failure, ultimately leading to aneuploidy, is appreciated as an early step in tumor formation in mammals and is deleterious for all cells. Further, the growing list of cancer predisposition mutations includes a number of genes whose proteins control mitosis and/or cytokinesis. Cytokinesis shape control is also an important part of pattern formation and cell-type specialization during multi-cellular development. Inherently mechanical, we hypothesized that mechanosensing and mechanical feedback are fundamental for cytokinesis shape regulation. Using mechanical perturbation, we identified a mechanosensory control system that monitors shape progression during cytokinesis. In this review, we summarize these findings and their implications for cytokinesis regulation and for understanding the cytoskeletal system architecture that governs shape control.

Figure 1

Stereotypical, open-loop cytokinesis. (A) Cartoon depicts the series of shapes that cells undergo during cytokinesis. Region of myosin-II enrichment is shown in green. Microtubules are shown in red and depict the microtubule rearrangements typical of Dictyostelium. Nuclei are shown as blue circles. Dictyostelium cells have a closed mitosis (similar to yeast) in which the nuclear envelope does not completely disassemble as in higher metazoans. (B) Diagram depicts an open loop system in which the mitotic spindle delivers signals that direct the accumulation of contractile proteins to the equatorial cortex. The contractile proteins generate force, which changes the cell shape until cytokinesis is completed, producing two daughter cells. However, mechanical perturbations can also affect the forces acting on the cell, and if these disturbances go undetected, cytokinesis can be defective.

Figure 2

Myosin-II redistributes to the site of cell deformation during anaphase through the end of cytokinesis. (A) Three examples of mitotic cells aspirated during anaphase. DIC images show the cell and the micropipette. RFP-tubulin images reveal anaphase spindles that are often bowed during the cell deformation. GFP-myosin-II becomes enriched under the micropipettes. Line scans show the increased GFP-myosin-II accumulation at the micropipette. (B) Three examples of late stage dividing cells aspirated by the micropipette (DIC). GFP-myosin-II has accumulated at the micropipette (arrows) and at the cleavage furrow cortex. Line scans show the increased GFP-myosin-II accumulation at the micropipette. Scale bars in (A and B) are 10 mm and apply to all panels.

Figure 3

Diagram depicts a mechanosensory system that monitors cell shape during cytokinesis. This system is closed loop in which cell shape is monitored and fed back to redirect contractile protein accumulation to regions of shape deformation. Upon correcting cell shape, the contractile proteins reaccumulate at the equatorial cortex, allowing symmetrical cell division to complete.

Figure 4

Classes of potential mechanosensors that could sense cellular deformation. (A) The actin network itself can function as a mechanosensor. Strain induced by applied force (F) on the network can lead to local unfolding of actin-associated proteins, which can create new binding sites, allowing other proteins (green ball) to associate. (B) Strain in the membrane can lead to channel opening, allowing ions to move. Many types of channels are known to be strain-sensitive. (C) Myosins are strain sensitive. Load against the motor increases the strongly bound state time (t_s) typically by inhibiting ADP-release for most myosin classes. If myosin binding changes the actin network, stabilizing actin-myosin interactions by increasing t_s could lead to accumulation of other actin-associated proteins.