Activator–inhibitor coupling between Rho signalling and actin assembly makes the cell cortex an excitable medium

Abstract

Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, while Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modeling results show that waves represent excitable dynamics of a reaction diffusion system with Rho as the activator and F-actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation.

Living Xenopus oocytes, eggs, and embryos as models for cell division

“…For example, the montage can reveal repetitive patterns in cortical waves of Rho activity and actin assembly–disassembly that might be overlooked when viewing the original movies (Bement et al, 2015). To make a montage, import the image stack and crop the area of interest by drawing a box and selecting “Image→Crop.” Then, create the montage by selecting “Image→Stacks→Make Montage” and specify the layout, scale, intervals, and increment.…”

“…5). Using faster and higher resolution imaging, it was found that the Xenopus cortex continuously generates waves of Rho activity that stimulate subsequent waves of actin assembly and disassembly (Bement et al, 2015; Fig. 6; see also below).…”

Clathrin Assembly Defines the Onset and Geometry of Cortical Patterning

“…At the single cell level, the collective dynamics of cortical actin have been documented in many cellular systems and are referred to as cortical waves. Understanding the cortical dynamics and the emergence of the collective dynamics within the cortex are critical for our understanding of cellular behaviours, such as polarity (Howell et al, 2012), migration (Weiner et al, 2007), mitosis (Bement et al, 2015), and cell growth (Das et al, 2012). …”

“…For cortical actin waves, molecular players that act upstream of actin, including Rho family GTPases and their activating lipid second messengers have been heavily investigated. These include Rac and phosphatidylinositol-3,4,5-trisphosphate (PIP3) in HL-60 neutrophils (Weiner et al, 2007), Rho in Xenopus eggs and starfish oocytes (Bement et al, 2015), PIP3 and phosphoinositide-3-kinase (PI3K) in Dictyostelium discoideum (Arai et al, 2010), and Cdc42 and PI3K in RBL-2H3 mast cells (Xiong et al, 2016). Because waves of Rho GTPase activation usually precedes actin waves and inactivation of these Rho GTPases could abolish actin waves, activation of Rho GTPases has been suggested to be involved in wave nucleation.…”

“…Yet, the mechanisms that mediate the spatiotemporal activation of Rho GTPases in the cortical waves remain obscure. Mathematically, the nucleation of a patch of activation of GTPases has been modeled as molecular “noise” amplified by positive feedback mechanisms (Bement et al, 2015; Dyer et al, 2013; Holmes et al, 2012; Ozbudak et al, 2005). …”