scholarly journals DISTINCT ACTIN-DEPENDENT NANOSCALE ASSEMBLIES UNDERLIE THE DYNAMIC AND HIERARCHICAL ORGANIZATION OF E-CADHERIN

2019 ◽  
Author(s):  
Rumamol Chandran ◽  
Girish Kale ◽  
Jean-Marc Philippe ◽  
Thomas Lecuit ◽  
Satyajit Mayor
Keyword(s):  
Ectopic Expression ◽  
Fluorescence Emission ◽  
Correlation Spectroscopy ◽  
Hierarchical Organization ◽  
Cell Junctions ◽  
Epithelial Tissue ◽  
Emission Anisotropy ◽  
Dynamic Organization ◽  
E Cadherin ◽  
Cell Cell

SUMMARYIntercellular adhesion mediated by E-cadherin is pivotal in maintaining epithelial tissue integrity and for tissue morphogenesis. Adhesion requires homophilic interactions between extracellular domains of E-cadherin molecules from neighboring cells. The interaction of its cytoplasmic domains with the cortical acto-myosin network, appears to strengthen adhesion, although, it is unclear how cortical actin affects the organization and function of E-cadherin dynamically. Here we use the ectopic expression of Drosophila E-cadherin (E-cad) in larval hemocytes, which lack endogenous E-cad, to recapitulate functional cell-cell junctions in a convenient model system. We used fluorescence emission anisotropy-based microscopy and Fluorescence Correlation Spectroscopy (FCS) to probe the nanoscale organization of E-cad. We find that E-cad at cell-cell junctions in hemocytes exhibits a clustered trans-paired organization, similar to that reported for the adherens junction in the developing embryonic epithelial tissue. Further, we find that extra-junctional E-cad is also organized as relatively immobile nanoclusters as well as diffusive and more loosely packed oligomers and monomers. These oligomers are promoted by cis-interactions of the ectodomain and, strikingly, their growth is constantly counteracted by cortical actomyosin. Oligomers in turn assist in generating nanoclusters that are stabilized by cortical acto-myosin. Thus, actin remodels oligomers and stabilizes nanoclusters, revealing a requirement for actin in the dynamic organization of E-cad at the nanoscale. This dynamic organization is also present at cell-cell contacts (junction), and its disruption affects junctional integrity in the hemocyte system, as well as in the embryo. Our observations uncover a hierarchical mechanism for the nanoscale organization of E-cad, which is necessary for dynamic adhesion and maintaining junctional integrity in the face of extensive remodeling.

scholarly journals Formin-mediated actin polymerization at cell–cell junctions stabilizes E-cadherin and maintains monolayer integrity during wound repair

2016 ◽  
Vol 27 (18) ◽  
pp. 2844-2856 ◽  
Author(s):  
Megha Vaman Rao ◽  
Ronen Zaidel-Bar
Keyword(s):  
Cell Adhesion ◽  
Wound Repair ◽  
Actin Polymerization ◽  
Cell Junctions ◽  
Epithelial Tissue ◽  
Collective Cell Migration ◽  
Epithelial Junctions ◽  
Major Factors ◽  
E Cadherin ◽  
Cell Cell

Cadherin-mediated cell–cell adhesion is required for epithelial tissue integrity in homeostasis, during development, and in tissue repair. E-cadherin stability depends on F-actin, but the mechanisms regulating actin polymerization at cell–cell junctions remain poorly understood. Here we investigated a role for formin-mediated actin polymerization at cell–cell junctions. We identify mDia1 and Fmnl3 as major factors enhancing actin polymerization and stabilizing E-cadherin at epithelial junctions. Fmnl3 localizes to adherens junctions downstream of Src and Cdc42 and its depletion leads to a reduction in F-actin and E-cadherin at junctions and a weakening of cell–cell adhesion. Of importance, Fmnl3 expression is up-regulated and junctional localization increases during collective cell migration. Depletion of Fmnl3 or mDia1 in migrating monolayers results in dissociation of leader cells and impaired wound repair. In summary, our results show that formin activity at epithelial cell–cell junctions is important for adhesion and the maintenance of epithelial cohesion during dynamic processes, such as wound repair.

scholarly journals Epithelial self-healing is recapitulated by a 3D biomimetic E-cadherin junction

2016 ◽  
Vol 113 (51) ◽  
pp. 14698-14703 ◽  
Author(s):  
Daniel J. Cohen ◽  
Martijn Gloerich ◽  
W. James Nelson
Keyword(s):  
Epithelial Cell ◽  
Vertical Surface ◽  
Stop Signal ◽  
Cell Junctions ◽  
Epithelial Tissue ◽  
Self Healing ◽  
Material Interfaces ◽  
Cell Adhesions ◽  
E Cadherin ◽  
Cell Cell

Epithelial monolayers undergo self-healing when wounded. During healing, cells collectively migrate into the wound site, and the converging tissue fronts collide and form a stable interface. To heal, migrating tissues must form cell–cell adhesions and reorganize from the front-rear polarity characteristic of cell migration to the apical-basal polarity of an epithelium. However, identifying the "stop signal" that induces colliding tissues to cease migrating and heal remains an open question. Epithelial cells form integrin-based adhesions to the basal extracellular matrix (ECM) and E-cadherin–mediated cell–cell adhesions on the orthogonal, lateral surfaces between cells. Current biological tools have been unable to probe this multicellular 3D interface to determine the stop signal. We addressed this problem by developing a unique biointerface that mimicked the 3D organization of epithelial cell adhesions. This "minimal tissue mimic" (MTM) comprised a basal ECM substrate and a vertical surface coated with purified extracellular domain of E-cadherin, and was designed for collision with the healing edge of an epithelial monolayer. Three-dimensional imaging showed that adhesions formed between cells, and the E-cadherin-coated MTM resembled the morphology and dynamics of native epithelial cell–cell junctions and induced the same polarity transition that occurs during epithelial self-healing. These results indicate that E-cadherin presented in the proper 3D context constitutes a minimum essential stop signal to induce self-healing. That the Ecad:Fc MTM stably integrated into an epithelial tissue and reduced migration at the interface suggests that this biointerface is a complimentary approach to existing tissue–material interfaces.

(Tissue) P systems with cell polarity

2009 ◽  
Vol 19 (6) ◽  
pp. 1141-1160 ◽  
Author(s):  
DANIELA BESOZZI ◽  
NADIA BUSI ◽  
PAOLO CAZZANIGA ◽  
CLAUDIO FERRETTI ◽  
ALBERTO LEPORATI ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Formal System ◽  
Cell Junctions ◽  
P Systems ◽  
Intestinal Lumen ◽  
Epithelial Tissue ◽  
Specific Cell ◽  
Formal Property ◽  
Intestinal Epithelial ◽  
Cell Cell

We consider the structure of the intestinal epithelial tissue and of cell–cell junctions as the biological model inspiring a new class of P systems. First we define the concept of cell polarity, a formal property derived from epithelial cells, which present morphologically and functionally distinct regions of the plasma membrane. Then we show two preliminary results for this new model of computation: on the theoretical side, we show that P systems with cell polarity are computationally (Turing) complete; on the modelling side, we show that the transepithelial movement of glucose from the intestinal lumen into the blood can be described by such a formal system. Finally, we define tissue P systems with cell polarity, where each cell has fixed connections to the neighbouring cells and to the environment, according to both the cell polarity and specific cell–cell junctions.

scholarly journals HGF Converts ErbB2/Neu Epithelial Morphogenesis to Cell Invasion

2005 ◽  
Vol 16 (2) ◽  
pp. 550-561 ◽  
Author(s):  
Hanane Khoury ◽  
Monica A. Naujokas ◽  
Dongmei Zuo ◽  
Veena Sangwan ◽  
Melanie M. Frigault ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Invasion ◽  
Single Cells ◽  
Epithelial Morphogenesis ◽  
Cell Junctions ◽  
Junction Protein ◽  
Hepatocyte Growth ◽  
E Cadherin ◽  
Cell Cell

Activation of the hepatocyte growth factor receptor Met induces a morphogenic response and stimulates the formation of branching tubules by Madin-Darby canine kidney (MDCK) epithelial cells in three-dimensional cultures. A constitutively activated ErbB2/Neu receptor, NeuNT, promotes a similar invasive morphogenic program in MDCK cells. Because both receptors are expressed in breast epithelia, are associated with poor prognosis, and hepatocyte growth factor (HGF) is expressed in stroma, we examined the consequence of cooperation between these signals. We show that HGF disrupts NeuNT-induced epithelial morphogenesis, stimulating the breakdown of cell-cell junctions, dispersal, and invasion of single cells. This correlates with a decrease in junctional proteins claudin-1 and E-cadherin, in addition to the internalization of the tight junction protein ZO-1. HGF-induced invasion of NT-expressing cells is abrogated by pretreatment with a pharmacological inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway, which restores E-cadherin and ZO-1 at cell-cell junctions, establishing the involvement of MEK-dependent pathways in this process. These results demonstrate that physiological signals downstream from the HGF/Met receptor synergize with ErbB2/Neu to enhance the malignant phenotype, promoting the breakdown of cell-cell junctions and enhanced cell invasion. This is particularly important for cancers where ErbB2/Neu is overexpressed and HGF is a physiological growth factor found in the stroma.

scholarly journals Cortical Tension Initiates the Positive Feedback Loop Between E-cadherin and F-actin

2021 ◽  
Author(s):  
Qilin Yu ◽  
William R. Holmes ◽  
Jean P. Thiery ◽  
Rodney B. Luwor ◽  
Vijay Rajagopal
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Adherens Junctions ◽  
Force Balance ◽  
Intercellular Junction ◽  
Cell Junctions ◽  
Positive Feedback Loop ◽  
Cortical Tension ◽  
E Cadherin ◽  
Cell Cell

AbstractAdherens junctions (AJs) physically link two cells at their contact interface via extracellular homophilic interactions between cadherin molecules and intracellular connections between cadherins and the actomyosin cortex. Both cadherin and actomyosin cytoskeletal dynamics are reciprocally regulated by mechanical and chemical signals, which subsequently determine the strength of cell-cell adhesions and the emergent organization and stiffness of the tissues they form. However, an understanding of the integrated system is lacking. We present a new mechanistic computational model of intercellular junction maturation in a cell doublet to investigate the mechano-chemical crosstalk that regulates AJ formation and homeostasis. The model couples a 2D lattice-based model of cadherin dynamics with a continuum, reaction-diffusion model of the reorganizing actomyosin network through its regulation by Rho signaling at the intercellular junction. We demonstrate that local immobilization of cadherin induces cluster formation in a cis less dependent manner. We further investigate how cadherin and actin regulate and cooperate. By considering the force balance during AJ maturation and the force-sensitive property of the cadherin/F-actin linking molecules, we show that cortical tension applied on the contact rim can explain the ring distribution of cadherin and F-actin on the cell-cell contact of the cell-doublet. Meanwhile, the positive feedback loop between cadherin and F-actin is necessary for maintenance of the ring. Different patterns of cadherin distribution can be observed as an emergent property of disturbances of this feedback loop. We discuss these findings in light of available experimental observations on underlying mechanisms related to cadherin/F-actin binding and the mechanical environment.Significance StatementThe formation, maintenance and disassembly of adherens junctions (AJs) is fundamental to organ development, tissue integrity as well as tissue function. E-cadherins and F-actin are two major players of the adherens junctions (AJs). Although it is well known that cadherins and F-actin affect each other, how these two players work together to maintain the intercellular contact is unclear. Using a novel mechano-chemical model of E-cadherin and F-actin remodeling, we demonstrate that a positive feedback loop between cadherins and F-actin allows them to stabilize each other locally. Mechanical and chemical stimuli applied to the cell adhesion change E-cadherin and F-actin distribution by consolidating or interrupting the feedback loop locally. Our study mechanistically links mechanical force to E-cadherin patterning at cell-cell junctions.

scholarly journals Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue

Cell Reports ◽  
2016 ◽  
Vol 14 (1) ◽  
pp. 152-167 ◽  
Author(s):  
Zahra Erami ◽  
David Herrmann ◽  
Sean C. Warren ◽  
Max Nobis ◽  
Ewan J. McGhee ◽  
...  
Keyword(s):  
Cell Junctions ◽  
Dynamic Regulation ◽  
Live Tissue ◽  
Drug Dependent ◽  
E Cadherin ◽  
Cell Cell

The Basic Helix-Loop-Helix TAL1/SCL and Its Partners E47 and LMO2 Act Upstream of the VE-Cadherin Gene in Endothelial Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1795-1795
Author(s):  
Virginie Deleuze ◽  
Elias Chalhoub ◽  
Rawan El-Hajj ◽  
Christiane Dohet ◽  
Mikael Le Clech ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ectopic Expression ◽  
Cell Junctions ◽  
Small Interfering Rnas ◽  
Hek 293 ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Cell Cell

Abstract The basic helix-loop-helix protein TAL-1/SCL, essential for the formation of the hematopoietic system, is also required for vascular development and more particularly for embryonic angiogenesis. We previously reported that TAL-1 acts as a positive factor for post-natal angiogenesis by stimulating endothelial morphogenesis. To understand how TAL-1 modulates angiogenesis, we investigated the functional consequences of TAL-1 silencing, mediated by small-interfering RNAs, in human primary endothelial cells (ECs). We found that TAL-1 knockdown impaired in vitro EC tubulomorphogenesis (in 2-D on Matrigel or 3-D in collagen I gel), with the notable absence of cell-cell contacts, a prerequisite for morphogenesis initiation. This cellular deficiency was associated with a dramatic reduction in the vascular-endothelial (VE)-cadherin at intercellular junctions, the major component of endothelial adherens junctions. In contrast, PECAM (or CD31) was present at cell-cell junctions at the same levels as control cells. Importantly, silencing of two known TAL-1-partners in hematopoietic cells, E47 or LMO2, produce the same effects as TAL-1. Accordingly, silencing of TAL-1, as well as E47 and LMO2, provoked down-regulation of VE-cadherin at both the mRNA and protein levels. Transient transfection experiments in HUVECs showed that TAL-1 and E47 regulate the VE-cadherin promoter through a specialized E-box element. Finally, endogenous VE-cadherin transcription could be directly activated in non-endothelial HEK-293 cells that neither express TAL-1 or LMO2, by the sole concomitant ectopic expression of TAL-1, E47 and LMO2. Overall, our data demonstrate that a multiprotein complex containing at least TAL-1, LMO2 and E47 act upstream of the VE-cadherin gene. We are currently performing chromatin immunoprecipitation (ChIP) to investigate whether the TAL-1-containing complex binds in vivo the VE-cadherin promoter. This study identifies VE-cadherin as an upstream TAL-1-target gene in the endothelial lineage, and provides a first clue in TAL-1 function in the control of angiogenesis.

Cadmium (Cd2+) disrupts E-cadherin-dependent cell-cell junctions in MDCK cells

1997 ◽  
Vol 33 (7) ◽  
pp. 516-526 ◽  
Author(s):  
Walter C. Prozialeck ◽  
Peter C. Lamar
Keyword(s):  
Mdck Cells ◽  
Cell Junctions ◽  
Dependent Cell ◽  
E Cadherin ◽  
Cell Cell

Cadmium (Cd2+) disrupts Ca2+-dependent cell-cell junctions and alters the pattern of E-cadherin immunofluorescence in LLC-PK1 cells

1991 ◽  
Vol 181 (3) ◽  
pp. 1118-1124 ◽  
Author(s):  
Walter C. Prozialeck ◽  
Robert J. Niewenhuis
Keyword(s):  
Cell Junctions ◽  
Dependent Cell ◽  
E Cadherin ◽  
Cell Cell
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