Cortical forces and CDC-42 control clustering of PAR proteins for Caenorhabditis elegans embryonic polarization

Abstract

Cell polarization enables zygotes to acquire spatial asymmetry, which in turn patterns cellular and tissue axes during development. Local modification in the actomyosin cytoskeleton mediates spatial segregation of partitioning-defective (PAR) proteins at the cortex, but how mechanical changes in the cytoskeleton are transmitted to PAR proteins remains elusive. Here we uncover a role of actomyosin contractility in the remodelling of PAR proteins through cortical clustering. During embryonic polarization in Caenorhabditis elegans, actomyosin contractility and the resultant cortical tension stimulate clustering of PAR-3 at the cortex. Clustering of atypical protein kinase C (aPKC) is supported by PAR-3 clusters and is antagonized by activation of CDC-42. Cortical clustering is associated with retardation of PAR protein exchange at the cortex and with effective entrainment of advective cortical flows. Our findings delineate how cytoskeleton contractility couples the cortical clustering and long-range displacement of PAR proteins during polarization. The principles described here would apply to other pattern formation processes that rely on local modification of cortical actomyosin and PAR proteins.

The Drosophila Afadin and ZO-1 homologs Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling

“…Par3 and contractile myosin foci both are found in the anterior domain but they are interspersed rather than co-localizing. Par proteins regulate myosin contractility (Cheeks et al, 2004;Munro et al, 2004), while cortical myosin flow and contractility regulating Par protein polarization and clustering (Dickinson et al, 2017;Rodriguez et al, 2017;Wang et al, 2017). Our data are especially intriguing given the known role of Baz as a regulator of apicomedial actomyosin contractility in the Drosophila amnioserosa, where it regulates pulsatile contractions and the degree of coupling to cell shape change, via effects on atypical protein kinase C (aPKC; David et al, 2010;Durney et al, 2018).…”

Planar cell polarity in the C. elegans embryo emerges by differential retention of aPARs at cell-cell contacts

“…Vice versa, PAR-3 clustering has been shown to be required for effective advection (Dickinson et al, 2017). Moreover, consistent with CDC-42 activity shaping aPAR complexes, formation of clustered versus diffuse aPAR complexes during anteroposterior polarization also depends on an inverse activity state of PKC-3 (Rodriguez et al, 2017), giving rise to clustered PAR-3-PAR-6-PKC-3 inactive (corresponding to the co-clustered aPAR complex with CDC-42 low ; Wang et al, 2017) and diffuse CDC-42-PAR-6-PKC-3 active (corresponding to aPAR co-cluster dissociation or CDC-42 high , Wang et al, 2017). Although a different developmental stage, our data strongly support this type of aPAR complex regulation: In the first cell with planar polarized PAR-3 at cell-cell contacts, ABpl, we find that CDC-42 activity is presumably high in the posterior cell-cell contact due to the CDC-42-inactivating GAP, PAC-1, showing the reciprocal planar polarity of PAR-3 ( Figure 5A and C).…”

“…Recent reports about the differential functions of the different aPARs made us look more closely at the localization and its possible functions (Rodriguez et al, 2017;Wang et al, 2017). To this end we asked whether all aPARs show the same distribution and dynamics as PAR-6.…”

“…polarity determinants, adhesion or signaling complexes. Polarized activation of cortical flow and transient, avidity-driven interactions have been shown to lead to advection of anterior polarity factors (aPARs) PAR-3, PAR-6, and PKC-3, thereby establishing the anteroposterior axis in C. elegans (Munro et al, 2004;Goehring et al, 2011;Dickinson et al, 2017;Wang et al, 2017;Mittasch et al, 2018). In addition to patterning the anteroposterior axis, where longitudinal cortical flow is required, dorsoventral and left/right (l/r) patterning in C. elegans require rotational cortical flow (Singh and Pohl, 2014;Naganathan et al, 2014;Pohl, 2015;Sugioka and Bowerman, 2018).…”

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

“…Abbreviations used: HF, hair follicle; Ctrl, control. orthologs in C.elegans and Drosophila have previously been linked to actomyosin contractility [24][25][26][27] , albeit that the specific hierarchy among myosin activation and Par3 appears to be context-dependent. Based on the junctional localization of Par3 in keratinocytes 28 we hypothesized that the mitotic aberrations could be caused by a primary defect in generating spatiotemporal contractile stresses at cell-cell contacts.…”