Final Report Summary - BIOMECAMORPH (The Biomechanics of Epithelial Cell and Tissue Morphogenesis) The morphogenesis of animals and plants has fascinated scientists for decades. Embryologists, geneticists, cell biologists and now physicists have contributed a rich understanding of how multicellular organisms are formed. There are 3 major trends in the study of morphogenesis. A longstanding interest for the spatial control of cell identity/behaviour led to the identification of general principles of how information flow organizes morphogenesis. The cell biological foundation of morphogenesis emerged gradually and exploded 10 years ago with the advent of live imaging. The cell shape changes that underlie tissue invagination and extension were characterized: apical constriction, cell intercalation. Cell morphogenesis requires force generation and its spatial control by specific biochemical pathway. A more recent trend, fostered by a quantitative description of cell dynamics allows a quantitative/physical understanding of morphogenesis. The field of tissue morphogenesis is thus a broadly expanding and active, interdisciplinary research area. We have studied tissue morphogenesis in Drosophila and have advanced understanding of this complex process by studying three key problems. 1.Force generation. We studied the mechanisms of force generation in epithelial cells (subcellular scale).2. Force transmission. We investigated how force transmission yields cell shape changes (cell scale) 3. Integrating and orchestrating cell mechanics at the tissue level. We studied how force generation and transmission are integrated at the tissue scale to drive collective morphogenesis in a tissue. Under Aim1, we characterized how characterized actomyosin networks undergo cycles of assembly and disassembly (pulses) to cause cell deformations alternating with steps of stabilization to result in irreversible shape changes. Spatial control over MyoII exchange kinetics establishes two stable regimes of high and low dissociation rates, resulting in MyoII planar polarity. Pulsatility emerges at intermediate dissociation rates, enabling convergent advection of MyoII and its upstream regulators Rho1 GTP, Rok and MyoII phosphatase. Notably, pulsatility is not an outcome of an upstream Rho1 pacemaker. Rather, it is a self-organized system that involves positive and negative biomechanical feedback between MyoII advection and dissociation rates. Under Aim2, we developed a force sensor at E-cadherin junctions that enable a dynamic mapping of how tension remodel cell junctions. We also characterized the mechanisms underlying junction growth and its contribution to tissue extension. Under Aim3, we discovered the pivotal role of GPCR signalling in tissue morphogenesis. Polarized cell shape changes during tissue morphogenesis arise by controlling the subcellular distribution of Myosin II. For instance, during Drosophila gastrulation, apical constriction and cell intercalation is mediated by medial–apical Myosin II pulses that power deformations, and polarized accumulation of Myosin II that stabilizes these deformations. We reported the function of a common pathway comprising the heterotrimeric G proteins G#12/13, G#13F and G©1 in activating and polarizing Myosin II during Drosophila gastrulation. We propose that GPCR and G proteins constitute a general pathway for controlling actomyosin contractility in epithelia and that the activity of this pathway is polarized by tissue-specific regulators. The outcome of this work is a better understanding of how developmental pathways control cellular mechanics and thereby how they orchestrate tissue mechanics.
