Epithelial Viscoelasticity Is Regulated by Mechanosensitive E-cadherin Turnover

Abstract

Graphical AbstractHighlights d Mechanical stress releases p120-catenin from apical junctions d Loss of p120-catenin increases endocytic E-cadherin turnover d Loss of p120 speeds stress-dependent remodeling of the junctional network d Mechanical stress dependence of E-cadherin turnover sets tissue viscoelasticity SUMMARY Studying how epithelia respond to mechanical stresses is key to understanding tissue shape changes during morphogenesis. Here, we study the viscoelastic properties of the Drosophila wing epithelium during pupal morphogenesis by quantifying mechanical stress and cell shape as a function of time. We find a delay of 8 h between maximal tissue stress and maximal cell elongation, indicating a viscoelastic deformation of the tissue. We show that this viscoelastic behavior emerges from the mechanosensitivity of endocytic E-cadherin turnover. The increase in E-cadherin turnover in response to stress is mediated by mechanosensitive relocalization of the E-cadherin binding protein p120-catenin (p120) from cell junctions to cytoplasm. Mechanosensitivity of E-cadherin turnover is lost in p120 mutant wings, where E-cadherin turnover is constitutively high. In this mutant, the relationship between mechanical stress and stress-dependent cell dynamics is altered. Cells in p120 mutant deform and undergo cell rearrangements oriented along the stress axis more rapidly in response to mechanical stress. These changes imply a lower viscosity of wing epithelium. Taken together, our findings reveal that p120-dependent mechanosensitive E-cadherin turnover regulates viscoelastic behavior of epithelial tissues.

Endocytosis, cadherins and tissue dynamics

“…(B) Junctions between migrating astrocytes display planar-polarized dynamics where N-cadherin is endocytosed at the rear of the junctions, then recycled to the front is disrupted. Subtle changes in dorsal closure and wing size were observed in p120 ctn null Drosophila mutants, 26,27 but these animals were viable and fertile, consistent with observations in Caenorhabditis elegans mutant animals. 28 However, p120 ctn mutant animals were sensitized to the effects of cadherin or α-catenin alleles.…”

“…This was recently supported by in vivo studies conducted in the embryonic Drosophila wing. Here, Iyer et al identified a pool of DE‐cadherin that turned over on a minutes‐long time scale, consistent with the time scales for cadherin endocytosis. Notably, the mobile fraction of this cadherin pool was significantly increased in p120 ctn null mutants, implying that cadherin endocytosis was being increased.…”

Tissue rheology in embryonic organization

“…In zebrafish, these observations were further confirmed by the use of ferromagnetic oil droplets (FDs) to directly measure tissue viscosity within the PSM (Box 1; Fig 2F), pointing at the possibility that the mesoderm transits from a fluid into a more solid-like state during maturation along its anterior-posterior axis (Serwane et al, 2017;Mongera et al, 2018). Similarly, in the Drosophila pupal wing epithelium, the rate of cell elongation over time represents a reliable readout of the viscoelastic behaviour of the tissue during wing deformation (Iyer et al, 2019). For example, the viscosity of Xenopus embryonic tissues, when measured by explant shape analysis (ESA, Box 1), appears to be linearly correlated with the surface tension of the tissue, a relationship defined by the rate of cell rearrangements within the tissue (David et al, 2014).…”

“…By analysing variations in cell shape within the forming ventral furrow in Drosophila, solid-like areas within the furrow were shown to correspond to less elongated and variable cell shapes, while more fluid-like areas exhibit longer and more variable cell shape that allows more frequent cell rearrangements (Atia et al, 2018). Similarly, in the Drosophila pupal wing epithelium, the rate of cell elongation over time represents a reliable readout of the viscoelastic behaviour of the tissue during wing deformation (Iyer et al, 2019). While the theoretical considerations and experimental observations discussed above clearly show a link between certain cellular parameters, such as cell density, rearrangements and shape, with the tissue phase state and its resulting morphogenetic capacity, remarkably little is yet known on how these parameters are spatiotemporally regulated within the developing organism.…”

“…While most data so far support a permissive role of tissue material properties in tissue morphogenesis (Shook et al, 2018;Duda et al, 2019;Iyer et al, 2019), recent work also suggests that developing tissues can actively undergo pronounced changes in their material properties, modulating tissue shape changes (Petridou et al, 2019) and triggering other processes, such as cell migration . In some cases, these changes can be abrupt, thereby resembling phase transitions (i.e.…”