Orientation of cell divisions is a key mechanism of tissue morphogenesis. In the growing Drosophila wing imaginal disc epithelium, most of the cell divisions in the central wing pouch are oriented along the proximal-distal (P-D) axis by the Dachsous-Fat-Dachs planar polarity pathway. However, cells at the periphery of the wing pouch instead tend to orient their divisions perpendicular to the P-D axis despite strong Dachs polarization. Here, we show that these circumferential divisions are oriented by circumferential mechanical forces that influence cell shapes and thus orient the mitotic spindle. We propose that this circumferential pattern of force is not generated locally by polarized constriction of individual epithelial cells. Instead, these forces emerge as a global tension pattern that appears to originate from differential rates of cell proliferation within the wing pouch. Accordingly, we show that localized overgrowth is sufficient to induce neighbouring cell stretching and reorientation of cell division. Our results suggest that patterned rates of cell proliferation can influence tissue mechanics and thus determine the orientation of cell divisions and tissue shape.
Tissues can grow in a particular direction by controlling the orientation of cell divisions. This phenomenon is evident in the developing Drosophila wing epithelium, where the tissue becomes elongated along the proximal-distal axis. We show that orientation of cell divisions in the wing requires planar polarization of an atypical myosin, Dachs. Our evidence suggests that Dachs constricts cell-cell junctions to alter the geometry of cell shapes at the apical surface, and that cell shape then determines the orientation of the mitotic spindle. Using a computational model of a growing epithelium, we show that polarized cell tension is sufficient to orient cell shapes, cell divisions, and tissue growth. Planar polarization of Dachs is ultimately oriented by long-range gradients emanating from compartment boundaries, and is therefore a mechanism linking these gradients with the control of tissue shape.
Epithelial monolayers are one-cell thick tissue sheets that separate internal and external environments. As part of their function, they have to withstand extrinsic mechanical stresses applied at high strain rates. However, little is known about how monolayers respond to mechanical deformations. Here, by subjecting suspended epithelial monolayers to stretch, we find that they dissipate stresses on a minute timescale in a process that involves an increase in monolayer length, pointing to active remodelling of cell architecture during relaxation. Strikingly, monolayers consisting of tens of thousands of cells relax stress with similar dynamics to single rounded cells and both respond similarly to perturbations of actomyosin. By contrast, cell-cell junctional complexes and intermediate filaments do not relax tissue stress, but form stable connections between cells, allowing monolayers to behave rheologically as single cells. Taken together our data show that actomyosin dynamics governs the rheological properties of epithelial monolayers, dissipating applied stresses, and enabling changes in monolayer length. the Rosetrees Trust, the UCL Graduate School, the EPSRC funded doctoral training program CoMPLEX, and the European Research Council (ERC-CoG MolCellTissMech, agreement 647186 to GC). N.K. was in receipt of a UCL Overseas Research Scholarship. N.K. was supported by the Prof Rob Seymour Travel Bursary Fund for research visits to Barcelona. J.F. and A.B. were funded by BBSRC grant (BB/M003280 and BB/M002578) to G.
Morphogenesis is driven by small cell shape changes that modulate tissue organization. Apical surfaces of proliferating epithelial sheets have been particularly well studied. Currently, it is accepted that a stereotyped distribution of cellular polygons is conserved in proliferating tissues among metazoans. In this work, we challenge these previous findings showing that diverse natural packed tissues have very different polygon distributions. We use Voronoi tessellations as a mathematical framework that predicts this diversity. We demonstrate that Voronoi tessellations and the very different tissues analysed share an overriding restriction: the frequency of polygon types correlates with the distribution of cell areas. By altering the balance of tensions and pressures within the packed tissues using disease, genetic or computer model perturbations, we show that as long as packed cells present a balance of forces within tissue, they will be under a physical constraint that limits its organization. Our discoveries establish a new framework to understand tissue architecture in development and disease.
22The collective behaviour of cells in epithelial tissues is dependent on their 23 mechanical properties. However, the contribution of tissue mechanics to wound 24 90 cell-based models, such as vertex models 26,27 , have rarely been applied to replicate 91 in vivo wound healing dynamics. We model each cell in the tissue as a two-92 dimensional polygon carrying variable tension on their edges, with bulk elasticity and 93 peripheral contractility ( Supplementary Fig. 2a-b, methods). We parameterised the 94 model so that edges contacting the wound gradually increase in tension compared to 95 5 the surrounding tissue, to mimic the assembly of the contractile actomyosin purse 96 string, causing wound edge junctions to reduce in length. To capture experimentally 97 observed fluctuations in junctional and purse-string MyoII 28 , we introduced 98 fluctuations in line tension at cell-cell interfaces and in the purse-string 99 ( Supplementary Fig. 2d). Without introducing intercalation events into the model, 100 simulated wounds are unable to close (Figs. 2a, c, Supplementary Video 3). By 101 contrast, when intercalations are enabled in the model ( Supplementary Fig. 2c, see 102 methods), wounds are able to close (Figs. 2b, d, Supplementary Video 4), supporting 103 our hypothesis that intercalations at the wound edge are necessary to drive wound 104 closure. 105The vertex model predicts that in the absence of intercalation, cells around 106 the wound become more elongated towards the centre of the wound (Fig. 2e) than in 107 simulations with intercalations enabled (Fig. 2f). In both cases, the cells initially 108 elongate as the purse-string contracts the wound. As cells begin to intercalate away 109 from the wound edge their shapes relax, reducing the elongation over time. Towards 110 the end of wound closure, many intercalations occur (Fig. 2b), at which point the 111 elongation rapidly decreases, and the cells return to a fully relaxed state after healing 112 (Fig. 2f). With intercalations disabled, the cells remain highly elongated ( Fig. 2e). 113This led us to hypothesise that wound edge intercalations play a crucial role in 114 maintaining cell shape and tissue patterning. Indeed, wing disc cells appear regularly 115 packed immediately after wound closure (Fig. 3a) and the polygon distribution of 116 wound edge cells is restored upon healing (Fig. 3b). The seamless closure we 117 observe is distinct from a number of in vivo 22,29 and in vitro 5,30 systems that can form 118 visible scar-like rosette structures upon closure. To test our vertex model's prediction 119 that intercalation preserves cell shape, we quantified cell elongation in the first three 120 6 rows of cells away from the wound in wing discs ( Fig. 3c, Supplementary Video 5).
SummaryEpithelia grow and undergo extensive rearrangements to achieve their final size and shape. Imaging the dynamics of tissue growth and morphogenesis is now possible with advances in time-lapse microscopy, but a true understanding of their complexities is limited by automated image analysis tools to extract quantitative data. To overcome such limitations, we have designed a new open-source image analysis toolkit called EpiTools. It provides user-friendly graphical user interfaces for accurately segmenting and tracking the contours of cell membrane signals obtained from 4D confocal imaging. It is designed for a broad audience, especially biologists with no computer-science background. Quantitative data extraction is integrated into a larger bioimaging platform, Icy, to increase the visibility and usability of our tools. We demonstrate the usefulness of EpiTools by analyzing Drosophila wing imaginal disc growth, revealing previously overlooked properties of this dynamic tissue, such as the patterns of cellular rearrangements.
SummaryContact inhibition of locomotion (CIL) is a multifaceted process that causes many cell types to repel each other upon collision. During development, this seemingly uncoordinated reaction is a critical driver of cellular dispersion within embryonic tissues. Here, we show that Drosophila hemocytes require a precisely orchestrated CIL response for their developmental dispersal. Hemocyte collision and subsequent repulsion involves a stereotyped sequence of kinematic stages that are modulated by global changes in cytoskeletal dynamics. Tracking actin retrograde flow within hemocytes in vivo reveals synchronous reorganization of colliding actin networks through engagement of an inter-cellular adhesion. This inter-cellular actin-clutch leads to a subsequent build-up in lamellar tension, triggering the development of a transient stress fiber, which orchestrates cellular repulsion. Our findings reveal that the physical coupling of the flowing actin networks during CIL acts as a mechanotransducer, allowing cells to haptically sense each other and coordinate their behaviors.
The shape of a single animal cell is determined both by its internal cytoskeleton and through physical interactions with its environment. In a tissue context, this extracellular environment is made up largely of other cells and the extracellular matrix. As a result, the shape of cells residing within an epithelium will be determined both by forces actively generated within the cells themselves and by their deformation in response to forces generated elsewhere in the tissue as they propagate through cell-cell junctions. Together these complex patterns of forces combine to drive epithelial tissue morphogenesis during both development and homeostasis. Here we review the role of both active and passive cell shape changes and mechanical feedback control in tissue morphogenesis in different systems.
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