As forças contrácteis nos contatos tricelulares modulam a organização epitelial e a integridade da monocamada: mero acaso, fortuita necessidade ou design inteligente?

segunda-feira, maio 22, 2017

Contractile forces at tricellular contacts modulate epithelial organization and monolayer integrity

Julie Salomon, Cécile Gaston, Jérémy Magescas, Boris Duvauchelle, Danielle Canioni, Lucie Sengmanivong, Adeline Mayeux, Grégoire Michaux, Florence Campeotto, Julie Lemale, Jérôme Viala, Françoise Poirier, Nicolas Minc, Jacques Schmitz, Nicole Brousse, Benoit Ladoux, Olivier Goulet & Delphine Delacour

Nature Communications 8, Article number: 13998 (2017)

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Cell adhesion Mechanisms of disease

Received: 10 October 2016 Accepted: 17 November 2016

Published online: 13 January 2017


Monolayered epithelia are composed of tight cell assemblies that ensure polarized exchanges. EpCAM, an unconventional epithelial-specific cell adhesion molecule, is assumed to modulate epithelial morphogenesis in animal models, but little is known regarding its cellular functions. Inspired by the characterization of cellular defects in a rare EpCAM-related human intestinal disease, we find that the absence of EpCAM in enterocytes results in an aberrant apical domain. In the course of this pathological state, apical translocation towards tricellular contacts (TCs) occurs with striking tight junction belt displacement. These unusual cell organization and intestinal tissue defects are driven by the loss of actomyosin network homoeostasis and contractile activity clustering at TCs, yet is reversed by myosin-II inhibitor treatment. This study reveals that adequate distribution of cortical tension is crucial for individual cell organization, but also for epithelial monolayer maintenance. Our data suggest that EpCAM modulation protects against epithelial dysplasia and stabilizes human tissue architecture.


We thank Patrick Tounian from the Armand Trousseau Hospital paediatric gastroenterology department (Paris, France), Marc Bellaïche and Jean-Pierre Hugot from the Robert Debré Hospital paediatric gastroenterology department (Paris, France) for contributing to the CTE biopsy collection. We thank the CTE patients and their family, for allowing us to study biopsies. We thank Sylvie Robine, René-Marc Mège, Maud Dumoux and Anne-Lise Haenni for critical reading of the manuscript. We thank Gianluca Grenci and Mohammed Ashraf (Microfabrication facility, Mechanobiology Institute (MBI), National University of Singapore (NUS), Singapore) for the design and generation of silicon wafers. We thank Léo Veyrier, Thomas Eche, Vincent Leguillier and Victoria Djordjevic for technical help. We thank Sandra Colas and Vanessa Lory for their expertise (Unité de Recherche Clinique (URC), Necker Hospital, Paris, France). We thank Virginie Bazin from the Electron Microscopy facility of the Institut de Biologie Paris-Seine (IBPS, Paris) for the SEM sample preparation and technical assistance during acquisitions. We thank François Waharte from the Nikon centre imaging facility (Curie Institute, Paris). We thank Rémi Le Borgne (ImagoSeine) for cell monolayer sample preparation for transmission electron microscopy. Confocal microscopy analyses were performed in the ImagoSeine microscopy facility (Institut Jacques Monod, IJM). High-resolution 3D-SIM and SP8 confocal analyses were acquired in the Nikon centre imaging facility (Curie Institute, Paris). This work was supported by grants from the GEFLUC Paris-Ile de France ‘Les entreprises contre le cancer’, from the ‘Fondation pour la Recherche Médicale’, from the ‘Association pour la Recherche contre le Cancer’, from ‘La Ligue, Comité de Paris’, ‘Initiatives d’excellence’ (Idex ANR-11-IDEX-0005-02)—Labex «Who Am I?» (ANR-11-LABX-0071) and from the ‘Assistance Publique—Hôpitaux de Paris, AP-HP’ (Projets Hospitaliers de Recherche Clinique (PHRC) grants).

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Author notes

Julie Salomon, Cécile Gaston & Jérémy Magescas

These authors contributed equally to this work


Cell Adhesion and Mechanics, Institut Jacques Monod, CNRS UMR7592, Paris Diderot University, 75205 Paris, France

Julie Salomon, Cécile Gaston, Jérémy Magescas, Adeline Mayeux, Benoit Ladoux & Delphine Delacour

Department of Paediatric Gastroenterology, Hôpital Necker-Enfants Malades, Sorbonne Paris Cité, 75015 Paris, France

Julie Salomon, Florence Campeotto, Jacques Schmitz & Olivier Goulet

Morphogenesis, Homoeostasis and Pathologies, Institut Jacques Monod, CNRS UMR7592, Paris Diderot University, 75013 Paris, France

Boris Duvauchelle & Françoise Poirier

Department of Paediatric Anatomo-Pathology, Hôpital Necker-Enfants Malades, Sorbonne Paris Cité, 75015 Paris, France

Danielle Canioni & Nicole Brousse

Membrane Dynamics and Mechanics of Intracellular Signaling Laboratory, Institut Curie–Centre de Recherche, PSL Research University, 75005 Paris, France

Lucie Sengmanivong

Institut de Génétique et Développement de Rennes, CNRS UMR6290, 35000 Rennes, France

Grégoire Michaux

Laboratoire de Microbiologie EA 4065, Faculté de Pharmacie, Université Paris Descartes, 75005 Paris, France

Florence Campeotto

Department of Pediatric Nutrition and Gastroenterology, Armand-Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Institute of Cardiometabolism and Nutrition, Pierre et Marie Curie University, 75012 Paris, France

Julie Lemale

Department of Pediatric Gastroenterology, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Université Paris Diderot, Sorbonne Paris Cité, UMR843, 75019 Paris, France

Jérôme Viala

Cellular Spatial Organization, Institut Jacques Monod, CNRS UMR7592, Paris Diderot University, 75205 Paris, France

Nicolas Minc

Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore

Benoit Ladoux


J.S., C.G., J.M., B.D., A.M., L.S., G.M., B.L. and D.D. performed the experiments. D.C., F.C., J.L., J.V., N.B. and O.G. provided patient biopsies. F.P., J.S., N.B. and O.G. participated in interpretation of the experiments and discussion. J.S., C.G., J.M., N.M., B.L. and D.D. designed the experiments. J.S., C.G., J.M. and D.D. performed analyses. J.S. and D.D. coordinated the overall research and experiments, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Delphine Delacour.

A organização microtubular é "determinada" pelo formato de células epiteliais: mero acaso, fortuita necessidade ou design inteligente?

Microtubule organization is determined by the shape of epithelial cells

Juan Manuel Gomez, Lyubov Chumakova, Natalia A. Bulgakova & Nicholas H. Brown

Nature Communications 7, Article number: 13172 (2016)

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Drosophila Microtubules Morphogenesis

Received: 05 February 2016 Accepted: 08 September 2016

Published online: 25 October 2016

Figure 2: Changes in epidermal cell shape and MT organization correlate during embryogenesis.


Interphase microtubule organization is critical for cell function and tissue architecture. In general, physical mechanisms are sufficient to drive microtubule organization in single cells, whereas cells within tissues are thought to utilize signalling mechanisms. By improving the imaging and quantitation of microtubule alignment within developing Drosophila embryos, here we demonstrate that microtubule alignment underneath the apical surface of epithelial cells follows cell shape. During development, epidermal cell elongation and microtubule alignment occur simultaneously, but by perturbing cell shape, we discover that microtubule organization responds to cell shape, rather than the converse. A simple set of microtubule behaviour rules is sufficient for a computer model to mimic the observed responses to changes in cell surface geometry. Moreover, we show that microtubules colliding with cell boundaries zip-up or depolymerize in an angle-dependent manner, as predicted by the model. Finally, we show microtubule alignment responds to cell shape in diverse epithelia.


We thank J. Casal, J. Knoblich, S. Noselli, V. Riechmann, E. Piddini, D. St Johnston, D. Strutt for reagents and fly stocks, N. Lawrence and the Gurdon Institute Imaging Facility for help with 3D-SIM imaging, A. Maartens for critical reading of the manuscript, all members of the Brown lab for discussion throughout the work. This work was supported by grant BB/K00056X/1 from the UK Biotechnology, Biological Sciences Research Council. Gurdon Institute core funding was provided by the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492). L.C. was supported by the Royal Society of Edinburgh/Scottish Government.

Author information

Author notes

Natalia A. Bulgakova & Nicholas H. Brown

These authors contributed equally to this work.

Juan Manuel Gomez

Present address: Institute of Genetics, University of Cologne, Cologne 50674, Germany

Natalia A. Bulgakova

Present address: Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK


Department of Physiology, Development and Neuroscience, and the Gurdon Institute, The University of Cambridge, Cambridge CB2 3DY, UK

Juan Manuel Gomez, Natalia A. Bulgakova & Nicholas H. Brown

School of Mathematics and Maxwell Institute for Mathematical Sciences, The University of Edinburgh, Edinburgh EH9 3FD, UK

Lyubov Chumakova


J.M.G., N.A.B. and N.H.B. designed experiments, J.M.G. performed all experiments, L.C. did in silico modelling, and all authors contributed to writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Natalia A. Bulgakova or Nicholas H. Brown.

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Arquitetura complexa modular em torno de uma simples "caixa de ferramentas" de genes de padrão de asas: mero acaso, fortuita necessidade ou design inteligente?

Complex modular architecture around a simple toolkit of wing pattern genes

Steven M. Van Belleghem, Pasi Rastas, Alexie Papanicolaou, Simon H. Martin, Carlos F. Arias, Megan A. Supple, Joseph J. Hanly, James Mallet, James J. Lewis, Heather M. Hines, Mayte Ruiz, Camilo Salazar, Mauricio Linares, Gilson R. P. Moreira, Chris D. Jiggins, Brian A. Counterman, W. Owen McMillan & Riccardo Papa

Nature Ecology & Evolution 1, Article number: 0052 (2017)

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Comparative genomics Evolutionary genetics Mimicry

Received: 22 June 2016 Accepted: 13 December 2016

Published online: 30 January 2017

Figure 1: Geographical distribution, phylogeny and colour pattern diversity 
of the Heliconius erato adaptive radiation.


Identifying the genomic changes that control morphological variation and understanding how they generate diversity is a major goal of evolutionary biology. In Heliconius butterflies, a small number of genes control the development of diverse wing colour patterns. Here, we used full-genome sequencing of individuals across the Heliconius erato radiation and closely related species to characterize genomic variation associated with wing pattern diversity. We show that variation around colour pattern genes is highly modular, with narrow genomic intervals associated with specific differences in colour and pattern. This modular architecture explains the diversity of colour patterns and provides a flexible mechanism for rapid morphological diversification.

Recent adaptive radiations, such as the Heliconius butterflies 1 , Galápagos finches 2 and African cichlids 3 , offer insight into evolutionary and ecological forces that underlie diversification. Typically, ecological opportunities allow natural and sexual selection to drive adaptive change and speciation. At a genetic level, recruitment from ancient polymorphism, introgression of adaptive variants between populations and de novo mutation are important sources of variation. However, the genetic architecture of the traits under natural and sexual selection that facilitates rapid diversification remains largely unexplored.

In this study, we sequenced the genome of the Neotropical butterfly Heliconius erato and used re-sequence data from 116 additional individuals to dissect the architecture of genomic variation associated with their vividly coloured wing patterns. With over 400 different wing colour forms among 46 described species 4 , Heliconius represents one of the most visually diverse radiations in the animal kingdom and an excellent system for establishing a broad and integrative view of morphological diversification. The evolution of scale cells and the spatial coordinate system that controls wing pigmentation is a key innovation of the Lepidoptera. Wing patterns are often under strong natural and sexual selection, and these forces probably shape much of the pattern diversity we see among the more than 160,000 butterfly and moth species 5 .

In Heliconius, conspicuous wing patterns are important for signalling toxicity to potential predators 6 and play a role in mate selection 7 . Natural selection favors Mìllerian mimicry among toxic butterflies, resulting in convergence between co-occurring species, as well as geographic divergence between populations of the same species 8 . Among Heliconius butterflies, the genetic basis of this wing diversity has been studied for nearly 60 years and more than 30 Mendelian loci have been described 9 . Over the past decade, however, genetic research has shown that most of the complexity of colour variation across Heliconius is actually controlled by relatively few genes acting broadly across the fore- and hindwing 10,​11,​12,​13,​14,​15,​16 . These genes include the transcription factor optix 14,17 , the signalling ligand wntA 15 and the cell cycle regulator cortex 16 . Hence, these studies have revealed that a limited set of ‘toolkit’ 18 genes has been repeatedly used for both highly divergent and convergent phenotypes in Heliconius, as well as other butterfly and moth species 16,19,20 . However, the key to wing pattern variation in Heliconius is not within the genes themselves, which are strongly conserved at the amino acid level, but at nearby non-coding regions that control expression during wing development 14,​15,​16 .

Here, we sequenced the genomes of 15 distinctly coloured H. erato races and 8 closely related species to fully describe the regulatory architecture driving adaptive evolution of the major genes acting in Heliconius wing patterning (Fig. 1). Our genomic survey included samples obtained near seven transition zones of hybridizing H. erato races with divergent wing patterns (Fig. 2a). In these hybrid zones, the high rate of genetic admixture allows for detailed genotype by phenotype (G × P) association mapping to identify discrete genomic intervals associated with colour and pattern variation on Heliconius wings 21,22 . We then further investigated these intervals with a novel phylogenetic method for identifying conserved non-coding regions in closely related non-hybridizing races and species. This combined strategy of association mapping and phylogenetic inference resulted in a distinct set of narrow genomic intervals that corresponded to loci described in early crossing experiments 9 (Supplementary Table 1). All the intervals fell within non-coding regions adjacent to colour pattern genes that affect forewing band shape (wntAFig. 3), red pigmentation (optixFig. 4) and a yellow hindwing bar (cortexFig. 5). Our results underscore a highly modular regulatory architecture that provides a flexible mechanism for rapid morphological change (Fig. 6).


We thank A. Tapia for maintaining the H. erato genome line and for generating our mapping family, and M. Vargas and C. Rosales for Illumina library preparation. We acknowledge the University of Puerto Rico, the Puerto Rico INBRE grant P20 GM103475 from the National Institute for General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH); CNRS Nouraugues and CEBA awards (B.A.C.); National Science Foundation awards DEB-1257839 (B.A.C.), DEB-1257689 (W.O.M.), DEB-1027019 (W.O.M.); awards 1010094 and 1002410 from the Experimental Program to Stimulate Competitive Research (EPSCoR) program of the National Science Foundation (NSF) for computational resources; and the Smithsonian Institution. This research was supported in part by Lilly Endowment, Inc., through its support for the Indiana University Pervasive Technology Institute, and in part by the Indiana METACyt Initiative. The Indiana METACyt Initiative at IU is also supported in part by Lilly Endowment, Inc. 

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