scholarly journals Ectoderm to mesoderm transition by downregulation of actomyosin contractility

2019 ◽  
Author(s):  
Leily Kashkooli ◽  
David Rozema ◽  
Lina Espejo-Ramirez ◽  
Paul Lasko ◽  
François Fagotto
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Specific Property ◽  
Tissue Level ◽  
Small Gtpase ◽  
Collective Migration ◽  
Mesenchymal Transition ◽  
Cortical Tension ◽  
Actomyosin Contractility ◽  
Fundamental Process ◽  
Rock Inhibition

SummaryCollective migration of cohesive tissues is a fundamental process in morphogenesis, and is particularly well illustrated during gastrulation by the rapid and massive internalization of the mesoderm, which contrasts with the much more modest movements of the ectoderm. In the Xenopus embryo, the differences in morphogenetic capabilities of ectoderm and mesoderm can be connected to the intrinsic motility of individual cells, very low for ectoderm, highly for mesoderm. Surprisingly, we find these seemingly deep differences can be accounted for simply by differences in Rock-dependent actomyosin contractility. We show that Rock inhibition is sufficient to rapidly unleash motility in the ectoderm and confer it with mesoderm-like properties. In the mesoderm, this motility is dependent on two negative regulators of RhoA, the small GTPase Rnd1 and the RhoGAP Shirin/Dlc2/ArhGAP37. Both are absolutely essential for gastrulation. At the cellular and tissue level, the two regulators show overlapping yet distinct functions. They both contribute to decrease cortical tension and confer motility, but Shirin tends to increase tissue fluidity and stimulate dispersion, while Rnd1 tends to favour more compact collective migration. Thus, each is able to contribute to a specific property of the migratory behaviour of the mesoderm. We propose that the “ectoderm to mesoderm transition” is a prototypic case of collective migration driven by a downregulation of cellular tension, without the need for the complex changes traditionally associated with the epithelial to mesenchymal transition.

scholarly journals Ectoderm to mesoderm transition by down-regulation of actomyosin contractility

PLoS Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. e3001060
Author(s):  
Leily Kashkooli ◽  
David Rozema ◽  
Lina Espejo-Ramirez ◽  
Paul Lasko ◽  
François Fagotto
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Specific Property ◽  
Tissue Level ◽  
Small Gtpase ◽  
Collective Migration ◽  
Down Regulation ◽  
Mesenchymal Transition ◽  
Cortical Tension ◽  
Actomyosin Contractility ◽  
Rock Inhibition

Collective migration of cohesive tissues is a fundamental process in morphogenesis and is particularly well illustrated during gastrulation by the rapid and massive internalization of the mesoderm, which contrasts with the much more modest movements of the ectoderm. In the Xenopus embryo, the differences in morphogenetic capabilities of ectoderm and mesoderm can be connected to the intrinsic motility of individual cells, very low for ectoderm, highly for mesoderm. Surprisingly, we find that these seemingly deep differences can be accounted for simply by differences in Rho-kinases (Rock)-dependent actomyosin contractility. We show that Rock inhibition is sufficient to rapidly unleash motility in the ectoderm and confer it with mesoderm-like properties. In the mesoderm, this motility is dependent on 2 negative regulators of RhoA, the small GTPase Rnd1 and the RhoGAP Shirin/Dlc2/ArhGAP37. Both are absolutely essential for gastrulation. At the cellular and tissue level, the 2 regulators show overlapping yet distinct functions. They both contribute to decrease cortical tension and confer motility, but Shirin tends to increase tissue fluidity and stimulate dispersion, while Rnd1 tends to favor more compact collective migration. Thus, each is able to contribute to a specific property of the migratory behavior of the mesoderm. We propose that the “ectoderm to mesoderm transition” is a prototypic case of collective migration driven by a down-regulation of cellular tension, without the need for the complex changes traditionally associated with the epithelial-to-mesenchymal transition.

The role of DUBs in the post-translational control of cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz
Keyword(s):  
Cell Migration ◽  
Translational Control ◽  
Epithelial To Mesenchymal Transition ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Fundamental Process ◽  
Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

scholarly journals Neuralized regulates a travelling wave of Epithelium-to-Neural Stem Cell morphogenesis in Drosophila

2020 ◽  
Author(s):  
Chloé Shard ◽  
Juan Luna-Escalante ◽  
François Schweisguth
Keyword(s):  
Stem Cells ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Optic Lobe ◽  
E3 Ubiquitin Ligase ◽  
Tissue Level ◽  
Travelling Wave ◽  
Cell Morphogenesis ◽  
Apical Constriction ◽  
Mesenchymal Transition

AbstractMany tissues are produced during development by specialized progenitor cells emanating from epithelia via an Epithelial-to-Mesenchymal Transition (EMT). Most studies have so far focused on cases involving single or isolated groups of cells. Here we describe an EMT-like process that requires tissue level coordination. This EMT-like process occurs along a continuous front in the Drosophila optic lobe neuroepithelium to produce neural stem cells (NSCs). We find that emerging NSCs remain epithelial and apically constrict before dividing asymmetrically to produce neurons. Apical constriction is associated with contractile myosin pulses and requires the E3 ubiquitin ligase Neuralized and RhoGEF3. Neuralized down-regulates the apical protein Crumbs via its interaction with Stardust. Disrupting the regulation of Crumbs by Neuralized led to defects in apical constriction and junctional myosin accumulation, and to imprecision in the integration of emerging NSCs into the transition front. Neuralized therefore appears to mechanically couple NSC fate acquisition with cell-cell rearrangement to promote smooth progression of the differentiation front.

scholarly journals Rac Inhibition As A Novel Therapeutic Strategy for EGFR/HER2 Targeted Therapy Resistant Breast Cancer

2020 ◽  
Author(s):  
Luis D Borrero-Garcia ◽  
Maria del Mar Maldonado ◽  
Julia I Medina-Velázquez ◽  
Angel Troche-Torres ◽  
Luis Velazquez-Vega ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Epithelial To Mesenchymal Transition ◽  
Point Mutations ◽  
Therapy Resistance ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intrinsic Resistance ◽  
Mesenchymal Transition ◽  
Resistant Cells

Abstract Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the parental cells, but not in the therapy resistant variants, indicating enhanced cancer stem cell-like and epithelial to mesenchymal transition (EMT) characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in established therapy resistant pathways of Akt and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer.

scholarly journals The EMT transcription factor Snai1 maintains myocardial wall integrity by repressing intermediate filament gene expression

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alessandra Gentile ◽  
Anabela Bensimon-Brito ◽  
Rashmi Priya ◽  
Hans-Martin Maischein ◽  
Janett Piesker ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intermediate Filament ◽  
Epithelial To Mesenchymal Transition ◽  
Intercellular Junctions ◽  
Wild Type ◽  
Cardiac Morphogenesis ◽  
Mesenchymal Transition ◽  
Myocardial Wall ◽  
Actomyosin Contractility ◽  
Valve Formation

The transcription factor Snai1, a well-known regulator of epithelial-to-mesenchymal transition, has been implicated in early cardiac morphogenesis as well as in cardiac valve formation. However, a role for Snai1 in regulating other aspects of cardiac morphogenesis has not been reported. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that Snai1b is required in cardiomyocytes for myocardial wall integrity. Loss of snai1b increases the frequency of cardiomyocyte extrusion away from the cardiac lumen. Extruding cardiomyocytes exhibit increased actomyosin contractility basally as revealed by enrichment of p-myosin and α-catenin epitope α-18, as well as disrupted intercellular junctions. Transcriptomic analysis of wild-type and snai1b mutant hearts revealed the dysregulation of intermediate filament genes, including desmin b (desmb) upregulation. Cardiomyocyte-specific desmb overexpression caused increased cardiomyocyte extrusion, recapitulating the snai1b mutant phenotype. Altogether, these results indicate that Snai1 maintains the integrity of the myocardial epithelium, at least in part by repressing desmb expression.

scholarly journals Tissue-wide coordination of epithelium-to-neural stem cell transition in the Drosophila optic lobe requires Neuralized

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Chloé Shard ◽  
Juan Luna-Escalante ◽  
François Schweisguth
Keyword(s):  
Stem Cells ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Optic Lobe ◽  
E3 Ubiquitin Ligase ◽  
Tissue Level ◽  
Apical Constriction ◽  
Mesenchymal Transition ◽  
Crumbs Complex ◽  
Cell Transition

Many tissues are produced by specialized progenitor cells emanating from epithelia via epithelial-to-mesenchymal transition (EMT). Most studies have so far focused on EMT involving single or isolated groups of cells. Here we describe an EMT-like process that requires tissue-level coordination. This EMT-like process occurs along a continuous front in the Drosophila optic lobe neuroepithelium to produce neural stem cells (NSCs). We find that emerging NSCs remain epithelial and apically constrict before dividing asymmetrically to produce neurons. Apical constriction is associated with contractile myosin pulses and involves RhoGEF3 and down-regulation of the Crumbs complex by the E3 ubiquitin ligase Neuralized. Anisotropy in Crumbs complex levels also results in accumulation of junctional myosin. Disrupting the regulation of Crumbs by Neuralized lowered junctional myosin and led to imprecision in the integration of emerging NSCs into the front. Thus, Neuralized promotes smooth progression of the differentiation front by coupling epithelium remodeling at the tissue level with NSC fate acquisition.

scholarly journals “Neur”al brain wave: Coordinating epithelial-to-neural stem cell transition in the fly optic lobe

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Arnaud Ambrosini ◽  
Katja Röper
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Optic Lobe ◽  
Tissue Level ◽  
Cell Alignment ◽  
Brain Wave ◽  
Apical Constriction ◽  
Mesenchymal Transition ◽  
Cell Behaviors ◽  
Crumbs Complex ◽  
Cell Transition

In the Drosophila larval optic lobe, the generation of neural stem cells involves an epithelial-to-mesenchymal–like transition of a continuous stripe of cells that sweeps across the neuroepithelium, but the dynamics at cell and tissue level were unknown until now. In this issue, Shard et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202005035) identify that Neuralized controls a partial epithelial-to-mesenchymal transition through regulation of the apical Crumbs complex and through the coordination of cell behaviors such as apical constriction and cell alignment.

scholarly journals Identification of phenotype-specific networks from paired gene expression-cell shape imaging data

2021 ◽  
Author(s):  
Charlie George Barker ◽  
Eirini Petsalaki ◽  
Girolamo Giudice ◽  
Emmanuel Nsa Ekpenyong ◽  
Chris Bakal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Shape ◽  
Epithelial To Mesenchymal Transition ◽  
Systems Approach ◽  
Small Gtpase ◽  
Mechanical Stimuli ◽  
Imaging Data ◽  
Network Systems ◽  
Mesenchymal Transition ◽  
A Cell

SummaryThe morphology of breast cancer cells is often used as an indicator of tumour severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes in order to undergo epithelial-to-mesenchymal transition and consequently metastase. However, the exact regulatory systems that define these changes remain poorly characterised. In this study, we employ a network-systems approach to integrate imaging data and RNA-seq expression data. By constructing a cell-shape signaling network from shape-correlated gene expression modules and their upstream regulators, we found central roles for development pathways such as Wnt and Notch as well as evidence for the fine control of NFkB signaling by numerous kinase and transcriptional regulators. Further analysis of our network implicates the small GTPase, Rap1 as a potential mediator between the sensing of mechanical stimuli and regulation of NFkB activity. Overall, our analysis provides mechanistic information on the interplay between cell signaling, gene regulation and cell morphology and our approach is generalisable to other cell phenotypes.

scholarly journals miR614 Expression Enhances Breast Cancer Cell Motility

2020 ◽  
Vol 22 (1) ◽  
pp. 112
Author(s):  
Tuyen T. Dang ◽  
Alec T. McIntosh ◽  
Julio C. Morales ◽  
Gray W. Pearson
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Epithelial To Mesenchymal Transition ◽  
Transmembrane Protein ◽  
Small Gtpase ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Intrinsic Gene ◽  
Increased Risk ◽  
Slug Expression

Using a data driven analysis of a high-content screen, we have uncovered new regulators of epithelial-to-mesenchymal transition (EMT) induced cell migration. Our results suggest that increased expression of miR614 can alter cell intrinsic gene expression to enhance single cell and collective migration in multiple contexts. Interestingly, miR614 specifically increased the expression of the EMT transcription factor Slug while not altering existing epithelial character or inducing other canonical EMT regulatory factors. Analysis of two different cell lines identified a set of genes whose expression is altered by the miR614 through direct and indirect mechanisms. Prioritization driven by functional testing of 25 of the miR614 suppressed genes uncovered the mitochondrial small GTPase Miro1 and the transmembrane protein TAPT1 as miR614 suppressed genes that inhibit migration. Notably, the suppression of either Miro1 or TAPT1 was sufficient to increase Slug expression and the rate of cell migration. Importantly, reduced TAPT1 expression correlated with an increased risk of relapse in breast cancer patients. Together, our results reveal how increased miR614 expression and the suppression of TAPT1 and Miro1 modulate the EMT state and migratory properties of breast cancer cells.

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