A tension-induced mechanotransduction pathway promotes epithelial morphogenesis (original) (raw)
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eLife, 2015
During development, biomechanical forces contour the body and provide shape to internal organs. Using genetic and molecular approaches in combination with a FRET-based tension sensor, we characterized a pulling force exerted by the elongating pharynx (foregut) on the anterior epidermis during C. elegans embryogenesis. Resistance of the epidermis to this force and to actomyosin-based circumferential constricting forces is mediated by FBN-1, a ZP domain protein related to vertebrate fibrillins. fbn-1 was required specifically within the epidermis and FBN-1 was expressed in epidermal cells and secreted to the apical surface as a putative component of the embryonic sheath. Tiling array studies indicated that fbn-1 mRNA processing requires the conserved alternative splicing factor MEC-8/RBPMS. The conserved SYM-3/FAM102A and SYM-4/WDR44 proteins, which are linked to protein trafficking, function as additional components of this network. Our studies demonstrate the importance of the apica...
Exploring the molecular basis for mechanosensation, signal transduction, and cytoskeletal remodeling
Acta Biomaterialia, 2005
Living cells respond to mechanical stimulation in a variety of ways that affect nearly every aspect of their function. Such responses can range from changes in cell morphology to activation of signaling cascades and changes in cell phenotype. Although the biochemical signaling pathways activated by mechanical stimulus have been extensively studied, little is known of the basic mechanisms by which mechanical force is transduced into a biochemical signal, or how the cell changes its behavior or properties in response to external or internal stresses. One hypothesis is that forces transmitted via individual proteins either at the site of cell adhesion to its surroundings or within the stress-bearing members of the cytoskeleton cause conformational changes that alter their binding affinity to other intracellular molecules. This altered equilibrium state can subsequently either initiate a biochemical signaling cascade or produce more immediate and local structural changes. To understand the phenomena related to mechanotransduction, the mechanics and chemistry of single molecules that form the signal transduction pathways must be examined. This paper presents a range of case studies that seek to explore the molecular basis of mechanical signal sensation and transduction, with particular attention to their macroscopic manifestation in the cell properties, e.g. in focal adhesion remodeling due to local application of force or changes in cytoskeletal rheology and remodeling due to cellular deformation.
Mechanochemical Signaling Directs Cell-Shape Change
Biophysical Journal, 2017
For specialized cell function, as well as active cell behaviors such as division, migration, and tissue development, cells must undergo dynamic changes in shape. To complete these processes, cells integrate chemical and mechanical signals to direct force production. This mechanochemical integration allows for the rapid production and adaptation of leading-edge machinery in migrating cells, the invasion of one cell into another during cell-cell fusion, and the force-feedback loops that ensure robust cytokinesis. A quantitative understanding of cell mechanics coupled with protein dynamics has allowed us to account for furrow ingression during cytokinesis, a model cell-shape-change process. At the core of cell-shape changes is the ability of the cell's machinery to sense mechanical forces and tune the force-generating machinery as needed. Force-sensitive cytoskeletal proteins, including myosin II motors and actin cross-linkers such as a-actinin and filamin, accumulate in response to internally generated and externally imposed mechanical stresses, endowing the cell with the ability to discern and respond to mechanical cues. The physical theory behind how these proteins display mechanosensitive accumulation has allowed us to predict paralogspecific behaviors of different cross-linking proteins and identify a zone of optimal actin-binding affinity that allows for mechanical stress-induced protein accumulation. These molecular mechanisms coupled with the mechanical feedback systems ensure robust shape changes, but if they go awry, they are poised to promote disease states such as cancer cell metastasis and loss of tissue integrity.
Polarity signaling balances epithelial contractility and mechanical resistance
Scientific Reports
Epithelia maintain a functional barrier during tissue turnover while facing varying mechanical stress. This maintenance requires both dynamic cell rearrangements driven by actomyosin-linked intercellular adherens junctions and ability to adapt to and resist extrinsic mechanical forces enabled by keratin filament-linked desmosomes. How these two systems crosstalk to coordinate cellular movement and mechanical resilience is not known. Here we show that in stratifying epithelia the polarity protein aPKCλ controls the reorganization from stress fibers to cortical actomyosin during differentiation and upward movement of cells. Without aPKC, stress fibers are retained resulting in increased contractile prestress. This aberrant stress is counterbalanced by reorganization and bundling of keratins, thereby increasing mechanical resilience. Inhibiting contractility in aPKCλ−/− cells restores normal cortical keratin networks but also normalizes resilience. Consistently, increasing contractile ...
2021
During embryonic morphogenesis, the integrity of epithelial tissues depends on the ability of cells in tissue sheets to undergo rapid changes in cell shape while preventing self-injury to junctional actin networks. LIM domain-containing repeat (LCR) proteins are recruited to sites of strained actin filaments in cultured cells, and are therefore promising candidates for mediating self-healing of actin networks, but whether they play similar roles in living organisms has not been determined. Here, we establish roles for Caenorhabditis elegans TES-1/Tes, an actin-binding LCR protein present at apical junctions, during epithelial morphogenesis. TES-1∷GFP is recruited to apical junctions during embryonic elongation, when junctions are under tension; in embryos in which stochastic failure of cell elongation occurs, TES-1 is only strongly recruited to junctions in cells that successfully elongate, and recruitment is severely compromised in genetic backgrounds in which cell shape changes do...
The role of actomyosin contractility at epithelial adherens junctions has been extensively studied. However, little is known about how external forces are integrated to establish epithelial cell and organ shape in vivo. We use the Drosophila follicle epithelium to investigate how tension at adherens junctions is regulated to integrate external forces arising from changes in germline size and shape. We find that overall tension in the epithelium decreases despite pronounced growth of enclosed germline cells, suggesting that the epithelium relaxes to accommodate growth. However, we find local differences in adherens junction tension correlate with apposition to germline nurse cells or the oocyte. We demonstrate that medial Myosin II coupled to corrugating adherens junctions resists nurse cell-derived forces and thus maintains apical surface areas and cuboidal cell shapes. Furthermore, medial reinforcement of the apical surface ensures cuboidal-to-columnar cell shape transitions and im...
Molecular mechanisms of cellular mechanosensing
Nature Materials, 2013
Mechanical forces direct a host of cellular and tissue processes. Although much emphasis has been placed on cell-adhesion complexes as force sensors, the forces must nevertheless be transmitted through the cortical cytoskeleton. Yet how the actin cortex senses and transmits forces and how cytoskeletal proteins interact in response to the forces is poorly understood. Here, by combining molecular and mechanical experimental perturbations with theoretical multi-scale modeling, we decipher cortical mechanosensing from molecular to cellular scales. We show that forces are shared between myosin II and different actin crosslinkers, with myosin having potentiating or inhibitory effects on certain crosslinkers. Different types of cell deformations elicit distinct responses, with myosin and α-actinin responding to dilation, and filamin mainly reacting to shear. Our observations show that the accumulation kinetics of each protein may be explained by its molecular mechanisms, and that protein accumulation and the cell's viscoelastic state can explain cell contraction against mechanical load. Cells are the ultimate smart material, being capable of self-renewal, self-repair and selfdefense through mechanisms that include the regulation of the cells' physical properties 1. To accomplish these features, cells must be able to sense and respond to mechanical inputs. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Appreciating the role of cell shape changes in the mechanobiology of epithelial tissues
Biophysics Reviews, 2022
The wide range of epithelial cell shapes reveals the complexity and diversity of the intracellular mechanisms that serve to construct their morphology and regulate their functions. Using mechanosensitive steps, epithelial cells can sense a variety of different mechanochemical stimuli and adapt their behavior by reshaping their morphology. These changes of cell shape rely on a structural reorganization in space and time that generates modifications of the tensional state and activates biochemical cascades. Recent studies have started to unveil how the cell shape maintenance is involved in mechanical homeostatic tasks to sustain epithelial tissue folding, identity, and self-renewal. Here, we review relevant works that integrated mechanobiology to elucidate some of the core principles of how cell shape may be conveyed into spatial information to guide collective processes such as epithelial morphogenesis. Among many other parameters, we show that the regulation of the cell shape can be...
Wnt/Frizzled Signaling Controls C. elegans Gastrulation by Activating Actomyosin Contractility
Current Biology, 2006
Background-Embryonic patterning mechanisms regulate the cytoskeletal machinery that drives morphogenesis, but there are few cases where links between patterning mechanisms and morphogenesis are well understood. We have used a combination of genetics, in vivo imaging, and cell manipulations to identify such links in C. elegans gastrulation. Gastrulation in C. elegans begins with the internalization of endodermal precursor cells in a process that depends on apical constriction of ingressing cells.