Drosophila wing discs show a remarkable variability when subject to mechanical perturbation. We developed a stretching bench that allows accurate measurements of instantaneous and time-dependent material behaviour of the disc as a whole, while determining the exact three-dimensional structure of the disc during stretching. Our experiments reveal force relaxation dynamics on timescales that are significant for development, along with a surprisingly nonlinear force-displacement relationship. Concurrently our imaging indicates that the disc is a highly heterogeneous tissue with a complex geometry. Using image-based 3D finite element modelling we are able to identify the contributions of size, shape and materials parameters to the measured force-displacement relations. In particular, we find that simulating the stretching of a disc with stiffness patterns in the extra-cellular matrix (ECM) recapitulates the experimentally found stretched geometries. In our simulations, linear hyperelasticity explains the measured nonlinearity to a surprising extent. To fully match the experimental force-displacement curves, we use an exponentially elastic material, which, when coupled to material relaxation also explains time-dependent experiments. Our simulations predict that as the disc develops, two counteracting effects, namely the discs foldedness and the hardening of the ECM lead to force-relative displacement curves that are nearly conserved during development.
Cadherin cell-cell adhesion proteins play critical roles in embryogenesis and in maintaining tissue integrity. Defects in cadherin adhesion occur in metastatic cancers. Cadherins mediate adhesion by binding in two conformations, X-dimers and strand-swap dimers. These binding conformations have distinctly different adhesive properties: while X-dimers form catch bonds that become longer-lived in the presence of a pulling force, strand-swap dimers form slip bonds that weaken upon pulling. It has been proposed that the cell, switches between X-dimer and strand-swap dimer conformations in order to regulate adhesion. However, little is known about the molecular mechanisms for these conformation changes and for cadherin adhesion regulation. Here, we use an integrated approach that couples live-cell, single molecule Atomic Force Microscope force measurements with precise, cell-biological manipulations of cadherin-cytoskeleton interactions, to characterize the biophysical mechanisms by which cadherins switch between alternate conformations on the cell surface and subsequently regulate adhesion. We demonstrate that cadherin interactions with the cytoskeleton tunes ectodomain conformation using an 'inside-out' mechanism. Our data also resolves the mechanistic details for mechanosensitive adhesion regulation.
Tissue morphogenesis integrates cell type-specific biochemistry and architecture, cellular force generation and mechanisms coordinating forces amongst neighbouring cells and tissues.We use finite element-based modelling to explore the interconnections at these multiple biological scales in embryonic dorsal closure, where pulsed actomyosin contractility in adjacent Amnioserosa (AS) cells powers the closure of an epidermis opening. Based on our in vivo observations, the model implements F-actin nucleation periodicity that is independent of MyoII activity. Our model reveals conditions, where depleting MyoII activity nevertheless indirectly affects oscillatory F-actin behaviour, without the need for biochemical feedback. In addition, it questions the previously proposed role of Dpp-mediated regulation of the patterned actomyosin dynamics in the AS tissue, suggesting them to be emergent. Tissue-specific Dpp interference supports the model's prediction. The model further predicts that the mechanical properties of the surrounding epidermis tissue feed back on the shaping and patterning of the AS tissue. Finally, our model's parameter space reproduces mutant phenotypes and provides predictions for their underlying cause. Our modelling approach thus reveals several unappreciated mechanistic properties of tissue morphogenesis.
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