Mechanosensitive Junction Remodeling Promotes Robust Epithelial Morphogenesis

Abstract

Morphogenesis of epithelial tissues requires tight spatiotemporal coordination of cell shape changes. In vivo, many tissue-scale shape changes are driven by pulsatile contractions of intercellular junctions, which are rectified to produce irreversible deformations. The functional role of this pulsatory ratchet and its mechanistic basis remain unknown. Here we combine theory and biophysical experiments to show that mechanosensitive tension remodeling of epithelial cell junctions promotes robust epithelial shape changes via ratcheting. Using optogenetic control of actomyosin contractility, we find that epithelial junctions show elastic behavior under low contractile stress, returning to their original lengths after contraction, but undergo irreversible deformation under higher magnitudes of contractile stress. Existing vertex-based models for the epithelium are unable to capture these results, with cell junctions displaying purely elastic or fluid-like behaviors, depending on the choice of model parameters. To describe the experimental results, we propose a modified vertex model with two essential ingredients for junction mechanics: thresholded tension remodeling and continuous strain relaxation. First, junctions must overcome a critical strain threshold to trigger tension remodeling, resulting in irreversible junction length changes. Second, there is a continuous relaxation of junctional strain that removes mechanical memory from the system. This enables pulsatile contractions to further remodel cell shape via mechanical ratcheting. Taken together, the combination of mechanosensitive tension remodeling and junctional strain relaxation provides a robust mechanism for large-scale morphogenesis.

Anisotropy links cell shapes to tissue flow during convergent extension

“…Consistent with the notion of additional barriers to cell rearrangement, recent work suggests that local remodeling of active junctional tension at cell-cell contacts only occurs above a critical strain threshold in cultured epithelial cells (59,62). This is consistent with a growing body of work that points toward important roles for membrane trafficking and E-cadherin turnover in junctional remodeling during Drosophila epithelial morphogenesis (11,(63)(64)(65).…”

Mechanical heterogeneity along single cell-cell junctions is driven by lateral clustering of cadherins during vertebrate axis elongation

“…Our model involves (i) a local junction stiffness (or elasticity) modeled using a spring element, which is consistent with the pulsatile relaxation of v-junctions observed in Xenopus CE (Shindo and Wallingford, 2014); (ii) a dynamic rest length, recently shown to be important for modeling CE (Staddon et al, 2019); (iii) a viscoelastic parameter, / , dictated by the spring stiffness, , and the friction at the vertices, ; and (iv) a rest length exponent, , which describes the time dependence of plastic displacement of the vertices modeled with a piston ( Fig. 2A, B…”

Optogenetic Control of RhoA to Probe Subcellular Mechanochemical Circuitry

“…If fast kinetics is desired, we recommend using the iLID/SspB or TULIP system, as these provide high temporal resolution of RhoA activation. The RhoGEF in TULIPs associates within less than 10 s and dissociates within 30‐60 s (Cavanaugh et al., ; Oakes et al., ; Staddon et al., ; Strickland et al., ; Wagner & Glotzer, ); the iLID/SspB system shows similar association and dissociation kinetics (Meshik et al., ; O'Neill et al., ). Slower kinetic systems have been seen with the CRY2/CIBN light‐gated dimerization system.…”

“…). Recent optogenetic tools have subcellularly localized RhoA GEFs for RhoA activation in dividing (Wagner & Glotzer, ), nonadherent (Meshik, O'Neill, & Gautam, ; O'Neill et al., ), and adherent cells in culture (Oakes et al., ), and more recently in tissue both in culture (Cavanaugh, Staddon, Munro, Banerjee, & Gardel, ; Staddon, Cavanaugh, Munro, Gardel, & Banerjee, ; Valon, Marín‐Llauradó, Wyatt, Charras, & Trepat, ) and in vivo (Izquierdo, Quinkler, & Renzis, ; Krueger, Quinkler, Mortensen, Sachse, & Renzis, ). These studies have successfully probed the complex nature of RhoA‐mediated contractility on cell‐cell and cell‐matrix forces, in addition to deciphering mechanosensitive signaling pathways that regulate cellular morphology and tissue‐scale morphogenesis.…”

“…Oakes and colleagues used the system to probe the molecular basis of actin stress fiber elasticity in single cells, showing a zyxin‐dependent mechanism (Oakes et al., ). More recently, it was discovered that RhoA was sufficient to induce stable cell‐cell junction deformations past a critical strain threshold to trigger mechanosensitive endocytosis in epithelial monolayers (Cavanaugh et al., ; Staddon et al., ). Altogether, these studies show the diverse applications of the TULIP system.…”