Sorting at embryonic boundaries requires high heterotypic interfacial tension

Abstract

The establishment of sharp boundaries is essential for segregation of embryonic tissues during development, but the underlying mechanism of cell sorting has remained unclear. Opposing hypotheses have been proposed, either based on global tissue adhesive or contractile properties or on local signalling through cell contact cues. Here we use ectoderm–mesoderm separation in Xenopus to directly evaluate the role of these various parameters. We find that ephrin-Eph-based repulsion is very effective at inducing and maintaining separation, whereas differences in adhesion or contractility have surprisingly little impact. Computer simulations support and generalise our experimental results, showing that a high heterotypic interfacial tension between tissues is key to their segregation. We propose a unifying model, in which conditions of sorting previously considered as driven by differential adhesion/tension should be viewed as suboptimal cases of heterotypic interfacial tension.

Actomyosin regulation by Eph receptor signaling couples boundary cell formation to border sharpness

“…By generating a series of point and deletion mutants of epha4, we find that forward signaling is essential for boundary marker expression, with a strong input of kinase-dependent signaling and lesser input of PDZ binding domain dependent signaling. These findings are consistent with studies of the regulation of cell repulsion and cortical tension by Eph receptor signaling (Canty et al, 2017;Fagotto et al, 2013;O'Neill et al, 2016;Rohani et al, 2011;Rohani et al, 2014;Taylor et al, 2017). Cell repulsion and tension are regulated by increased Rho activity, which leads to myosin light chain phosphorylation and actomyosin contraction at borders where Eph receptor activation is occurring (Fagotto et al, 2013;Rohani et al, 2014).…”

“…We find that for r3 and r5 they form on one side of each interface, in the epha4-expressing cells, and this is because they are induced by forward and not by reverse signaling. This finding is consistent with evidence that although reverse signaling can trigger cell repulsion, forward signaling leads to much stronger cell repulsion and actomyosin contraction and thus has a dominant role in cell segregation and border sharpening (Canty et al, 2017;Fagotto et al, 2013;O'Neill et al, 2016;Rohani et al, 2011;Rohani et al, 2014;Taylor et al, 2017;Wu et al, 2019). However, rfng expression is also detected in some cells adjacent to r3 or r5 that are not expressing epha4, in particular at the r5/r6 border.…”

“…Eph receptors and ephrins that have a high affinity for each other are expressed in complementary domains in many tissues (Cayuso et al, 2015;Gale et al, 1996;Rohani et al, 2014), such that activation of forward and reverse signaling occurs at the interface. Eph receptor and ephrin signaling can drive cell segregation and border sharpening through multiple mechanisms that likely depend upon whether the tissue is epithelial or mesenchymal: by decreasing cell-cell adhesion (Fagotto et al, 2013;Solanas et al, 2011), by increasing cortical tension (Calzolari et al, 2014;Canty et al, 2017), or by triggering cell repulsion (Poliakov et al, 2008;Rohani et al, 2011;Taylor et al, 2017;Wu et al, 2019). In addition, Eph-ephrin signaling has been found to regulate cell differentiation in a number of tissues (reviewed by (Laussu et al, 2014;Wilkinson, 2014)).…”

Ectoderm to mesoderm transition by downregulation of actomyosin contractility

“…The Xenopus embryo offers the unique possibility to easily dissect specific tissues, prepare explants and/or dissociate them into single cells, thus allowing the study of intrinsic cell and tissue properties in the absence of confounding influences of other surrounding embryonic structures. Importantly, the morphogenetic events occurring during Xenopus gastrulation are recapitulated in isolated explants, and furthermore, even individual dissociated cells have characteristics that clearly relate to the properties of the corresponding tissues: Ectoderm cells show higher cortical stiffness, higher cell-cell adhesion, and are largely immotile, while the softer mesoderm cells spread and migrate when laid on a fibronectin (FN) substrate [2][3][4][5] . Note that the mesoderm is composed of different regions along the anterior-posterior axis, sequentially the mesendoderm, the prechordal mesoderm, and the posterior chordal mesoderm.…”

357 Occupational exposure to selenium compounds, its effect on biological parameters and markers of diabetes

“…In quantitative analogy to the surface tensiondriven separation of oil and water, cells of different types can sort by differential adhesion (32). Chemotaxis can also contribute to pattern formation as in sporulation in Dictyostelium, and signaling pathways themselves can provide chemotactic signals (33).…”