TEAM

Cell polarity and morphogenesis of epithelia

Group leader : A. Le Bivic

Our project aims to understand the mechanisms that control the polarized organization of epithelial cells and the role of polarity complexes in the formation and maintenance of this organization. We are particularly interested in the role of the subapical cytoskeleton and in the evolution of this organization in the metazoan branch. In the long term, these studies will allow us to better understand how these mechanisms have emerged in the animal evolution and how deregulation of the epithelial layers organization is disturbed during, for example, the carcinogenesis process.

FOR BEGINNERS

Epithelia are involved in animal homeostasis by forming a barrier between the external and internal compartments. The establishment of epithelial layers requires the coordination of polarity complexes that are essential to define the apical surface in contact with the external environment and the lateral surface where intercellular junctions are positioned. In epithelial cells, the establishment of the plasma membrane specialized areas and of corresponding junctions at the border of these areas is accompanied by cytoskeletal organization of the subapical area to withstand tissue stresses and to anchor the microvilli of the apical pole. Our group investigates what molecular factors are essential for this apical organization and how polarity complexes are involved in this process. For that, we focus on the role of the Crumbs and Par6/aPKC complex in the establishment and maintenance of the apical pole in epithelial cells of the human intestine (enterocytes) and of the pupal wing Drosophila. Another aspect of the apical membrane specification is the formation of the primary cilium and many genes regulating cilia formation are also the cause of ciliopathies when mutated. The primary cilium is essential for many signalling pathways and the role of polarity complexes in its formation has been demonstrated. We thus study the role of the Crumbs and aPKC/Par6 complex in a model of epithelial cells from human retina and Xenopus embryonic ectoderm.

FOR SPECIALISTS

Our work focuses on two main issues of life science:

How epithelial structures that have led to the emergence of all multicellular animals has emerged during the evolution. This stage of evolution required the invention of new protein complexes necessary for cell cohesion and its modulation during morphogenetic movements and morphogenic signals of cell and tissue specification. The emergence of the Crumbs complex in the metazoan phylum and its functions in the organization and maintenance of epithelial junctions that emerge simultaneously (complex Cadherins) corresponds to expected complexes to pass this course of animal evolution.

The other major issue addressed byour work is the regulation of epithelial homeostasis, which is essential to animal life. This homeostasis is challenged during carcinogenic events and it should be remembered that the epithelia are responsible for 80% of cancers in adult men. It is now accepted that defects in expression or localization of polarity complexes induce disturbances of epithelial organization and are precancerous events. More generally, epithelium are privileged targets for many diseases such as cystic fibrosis or pathogens infection (viruses and bacteria).

Our group focuses on cellular and tissular causes of two diseases, either directly linked to Crumbs complex (retinitis pigmentosa) or linked to apical cytoskeletal organization (intestival microvillus inclusions). It has been shown in 1999, by the group of F. Cremers from Nimègue, that the CRB1 gene (Crumbs1) is responsible for diseases of the retina in humans, which are described under the names of Leber congenital amaurosis (LCA) and Retinitis pigmentosa type 12 (RP12). This disease has been mimicked in mice whith CRB1 gene mutation, which prove its role in this process. Our aim in the context of a collaborative research work with the group of J. Wijnholds in Amsterdam is to understand how the loss of Crumbs1 can induce retinal degeneration and how therapy can be considered in humans to prevent this degeneration. The other pathology we are studying is the microvillus inclusion disease  (MID), a disease of the newborn intestine and is mainly caused by mutations in the myosin Vb, a subapical component of the cytoskeleton. In this context we study the role of Drebrin, a protein binding actin in the apical domain organization and whose depletion in human intestinal cells strongly mimics the loss of function of Myosin Vb.Drebrine is therefore a good candidate to explain the formation defects in the apical membrane in MID.


Main publications

PUBLICATION

The elmo-mbc complex and rhogap19d couple Rho family GTPases during mesenchymal-to-epithelial-like transitions.

Toret CP, Shivakumar PC, Lenne PF, Le Bivic A.
Development. 2018 Feb 2. pii: dev.157495. doi: 10.1242/dev.157495. PMID: 29437779

PUBLICATION

Crumbs, Moesin and Yurt regulate junctional stability and dynamics for a proper morphogenesis of the Drosophila pupal wing epithelium.

Salis P, Payre F, Valenti P, Bazellieres E, Le Bivic A, Mottola G.
Sci Rep. 2017 Dec 1;7(1):16778. doi: 10.1038/s41598-017-15272-1. PMID: 29196707

PUBLICATION

Animal multicellularity and polarity without Wnt signaling.

Schenkelaars Q, Pratlong M, Kodjabachian L, Fierro-Constain L, Vacelet J, Le Bivic A, Renard E, Borchiellini C.
Sci Rep. 2017 Nov 13;7(1):15383. doi: 10.1038/s41598-017-15557-5. PMID: 29133828

PUBLICATION

Role of the crumbs proteins in ciliogenesis, cell migration and actin organization.

Bazellières E, Aksenova V, Barthélémy-Requin M, Massey-Harroche D, Le Bivic A.
Semin Cell Dev Biol. 2017 Oct 24. pii: S1084-9521(16)30333-0. doi: 10.1016/j.semcdb.2017.10.018. PMID: 29056580

PUBLICATION

The PCP pathway regulates Baz planar distribution in epithelial cells.

Aigouy B, Le Bivic A.
Sci Rep. 2016 Sep 14;6:33420. PMID: 27624969

PUBLICATION

Hook2, a microtubule-binding protein, interacts with Par6α and controls centrosome orientation during polarized cell migration.

Pallesi-Pocachard E, Bazellieres E, Viallat-Lieutaud A, Delgrossi MH, Barthelemy-Requin M, Le Bivic A, Massey-Harroche D.
Sci Rep. 2016 Sep 14;6:33259. PMID: 27624926

PUBLICATION

The Crumbs3 complex

B. Vacca, M. Barthélémy-Requin, C. Burcklé, D. Massey-Harroche and A. Le Bivic
Cell polarity 1: Biological Role and Basic Mechanisms. (K. Ebnet (Ed.). 2015: 51-63

PUBLICATION

Drebrin E depletion in human intestinal epithelial cells mimics Rab8a loss of function.

Vacca B, Bazellières E, Nouar R, Harada A, Massey-Harroche D, Le Bivic A.
Hum Mol Genet. 2014 Jan 12. PMID: 24399445

PUBLICATION

The multi-PDZ domain protein-1 (MUPP-1) expression regulates cellular levels of the PALS-1/PATJ polarity complex.

Assémat E, Crost E, Ponserre M, Wijnholds J, Le Bivic A, Massey-Harroche D.
Exp Cell Res. 2013 Oct 15;319(17):2514-25. PMID: 23880463

PUBLICATION

Evolution and Cell Physiology. 4. Why invent yet another protein complex to build junctions in epithelial cells?

Le Bivic A.
Am J Physiol Cell Physiol. 2013 Sep 11. PMID: 24025867
Other publications

PUBLICATION

Binding of ZO-1 to α5β1 integrins regulates the mechanical properties of α5β1-fibronectin links.

González-Tarragó V, Elosegui-Artola A, Bazellières E, Oria R, Pérez-González C, Roca-Cusachs P.
Mol Biol Cell. 2017 Jul 7;28(14):1847-1852. doi: 10.1091/mbc.E17-01-0006. PMID: 28251923

PUBLICATION

Quantitative methods to study epithelial morphogenesis and polarity

Aigouy B, Collinet C, Merkel M, Sagner A.
Methods Cell Biol. 2017;139:121-152. doi: 10.1016/bs.mcb.2016.12.004. PMID: 28215333

PUBLICATION

P-cadherin-mediated Rho GTPase regulation during collective cell migration.

Plutoni C, Bazellières E, Gauthier-Rouvière C.
Small GTPases. 2016 Jul 2;7(3):156-63. doi: 10.1080/21541248.2016.1173772. PMID: 27152729

PUBLICATION

The localisation of the apical Par/Cdc42 polarity module is specifically affected in microvillus inclusion disease.

Michaux G, Massey-Harroche D, Nicolle O, Rabant M, Brousse N, Goulet O, Le Bivic A, Ruemmele FM.
Biol Cell. 2016 Jan;108(1):19-28. PMID: 26526116

PUBLICATION

Segmentation and Quantitative Analysis of Epithelial Tissues.

Aigouy B, Umetsu D, Eaton S.
Methods Mol Biol. 2016;1478:227-239. PMID: 27730585

PUBLICATION

Draft Genome Sequence of an Alphaproteobacterium Associated with the Mediterranean Sponge Oscarella lobularis.

Jourda C, Santini S, Rocher C, Le Bivic A, Claverie JM.
Genome Announc. 2015 Sep 3;3(5). pii: e00977-15. PMID: 26337883

PUBLICATION

Mitochondrial Genome Sequence of the Glass Sponge Oopsacas minuta.

Jourda C, Santini S, Rocher C, Le Bivic A, Claverie JM.
Genome Announc. 2015 Jul 30;3(4). pii: e00823-15. PMID: 26227597

PUBLICATION

CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice.

Pellissier LP, Lundvig DM, Tanimoto N, Klooster J, Vos RM, Richard F, Sothilingam V, Garcia Garrido M, Le Bivic A, Seeliger MW, Wijnholds J.
Hum Mol Genet. 2014 Jul 15;23(14):3759-71. PMID: 24565864

PUBLICATION

Targeted Ablation of Crumbs1 and Crumbs2 in Retinal Progenitor Cells Mimics Leber Congenital Amaurosis.

Pellissier, L.P., Alves, C.H., Quinn, P.M., Vos, R.M., Tanimoto, N., Lundvig, D.M.S., Dudok, J.J., Hooibrink, B., Richard, F., Beck, S.C., Huber, G., Sothilingam, V., Garcia Garrido, M., Le Bivic, A., Seeliger, M.W. And Wijnholds,
PLoS Genet. 2013 Dec;9(12):e1003976. PMID: 24339791

PUBLICATION

Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton.

Ezan J, Lasvaux L, Gezer A, Novakovic A, May-Simera H, Belotti E, Lhoumeau AC, Birnbaumer L, Beer-Hammer S, Borg JP, Le Bivic A, Nürnberg B,Sans N, Montcouquiol M.
Nat Cell Biol. 2013 Sep;15(9):1107-15. PMID: 23934215

PUBLICATION

Loss of CRB2 in the mouse retina mimics human retinitis pigmentosa due to mutations in the CRB1 gene.

Alves CH, Sanz AS, Park B, Pellissier LP, Tanimoto N, Beck SC, Huber G, Murtaza M, Richard F, Sridevi Gurubaran I, Garcia Garrido M, Levelt CN, Rashbass P, Le Bivic A, Seeliger MW, Wijnholds J.
Hum Mol Genet. 2013 Jan 1;22(1):35-50. PMID: 23001562

Interactions

IBDM
NATIONAL
  • Carole Borchiellini (IMBE, Marseilles)
  • Jean-Michel Claverie (IGS, Marseilles)
  • Jean-Paul Borg (CRCM-IPC, Marseilles)
  • Grégoire Michaux (IGDR, Rennes)
  • Nicole Brousse (CHU Paris – Hôpital Necker-Enfants Malades)
  • Mireille Montcouquiol (INSERM-U862, Bordeaux)
  • Cécile Gauthier-Rouvière (CRBM, Montpellier)
  • Pascal Houillier (INSERM-UMRS 1138, Paris)
  • Pascal Chanez (INSERM 1067/CNRS 7333, Marseille)
INTERNATIONAL
  • Jan Wijnholds (LUMC, Leiden, Netherlands)
  • Vito Conte (IBEC, Barcelona, Spain)

Funding

Le Bivic team working on xenopus and drosophila melanogaster is funded by the INFORM network

ANR

ligue contre le cancer

Members more

Benoît Aigouy Magali Barthelemy Elsa Bazellieres Céline Burckle Pierre Mangeol Dominique Massey Harroche Juliette Raitiere   Christopher Toret  
André Le Bivic
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André Le Bivic

Researcher

Benoît Aigouy
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Benoît Aigouy

Researcher

Magali Barthelemy
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Magali Barthelemy

Technical staff

Elsa Bazellieres
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Elsa Bazellieres

Researcher

Céline Burckle
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Céline Burckle

University lecturer

Pierre Mangeol
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Pierre Mangeol

Researcher

Dominique Massey Harroche
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Dominique Massey Harroche

Researcher

Juliette Raitiere
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Juliette Raitiere

Technical staff

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Emmanuelle Renard

University lecturer

Christopher Toret
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Christopher Toret

Researcher

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Amelie Vernale

PhD student

Alumni

Pauline Salis, PHD, now PostDoc UMR 7232, Banyuls/mer.

Barbara Vacca, PHD, now PostDoc UCL, Londres.  

Annelise Viallat, engineer, now IE IBDM.

Richard Valli, engineer.

Giovanna Mottola, guest researcher, now MCU-PH UMR-MD2 AMU, Marseille.

Clément Ricard, Postdoc, now MCU UMR 8118, Paris.

Richard Roy, guest professeur, now Mac Gill, Canada.

Carole Baron Gaillard, Postdoc, now IR IBMC, Nice

Overview

Model organism
Biological process studied
  • Cell polarity and morphogenesis of epithelia
Medical applications
  • Retina degeneration
  • Microvillus inclusion disease
  • Cancer