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 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

PUBLICATION

Apico-basal elongation requires a drebrin-E-EB3 complex in columnar human epithelial cells.

Bazellières E, Massey-Harroche D, Barthélémy-Requin M, Richard F, Arsanto JP, Le Bivic A.
J Cell Sci. 2012 Feb 15;125(Pt 4):919-31. PMID: 22275434

PUBLICATION

Hook2 is involved in the morphogenesis of the primary cilium.

Baron Gaillard CL, Pallesi-Pocachard E, Massey-Harroche D, Richard F, Arsanto JP, Chauvin JP, Lecine P, Krämer H, Borg JP, Le Bivic A.
Mol Biol Cell. 2011 Dec;22(23):4549-62. PMID: 21998199

PUBLICATION

Crumbs proteins in epithelial morphogenesis.

Bazellieres E, Assemat E, Arsanto JP, Le Bivic A, Massey-Harroche D.

Front Biosci. 2009 Jan 1;14:2149-69. PMID: 19273190

PUBLICATION

Polarity complex proteins.

Assémat E, Bazellières E, Pallesi-Pocachard E, Le Bivic A, Massey-Harroche D.
Biochim Biophys Acta. 2008 Mar;1778(3):614-30. PMID: 18005931

PUBLICATION

Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex.

Massey-Harroche D, Delgrossi MH, Lane-Guermonprez L, Arsanto JP, Borg JP, Billaud M, Le Bivic A.
Hum Mol Genet. 2007 Mar 1;16(5):529-36. PMID: 17234746

PUBLICATION

PATJ connects and stabilizes apical and lateral components of tight junctions in human intestinal cells.

Michel D, Arsanto JP, Massey-Harroche D, Béclin C, Wijnholds J, Le Bivic A.
J Cell Sci. 2005 Sep 1;118(Pt 17):4049-57. PMID: 16129888

PUBLICATION

E-cadherin-mediated adhesion is not the founding event of epithelial cell polarity in Drosophila.

Le Bivic A.
Trends Cell Biol. 2005 May;15(5):237-40. PMID: 15866027

PUBLICATION

Role of Crumbs proteins in the control of epithelial cell and photoreceptor morphogenesis

Lemmers C, Médina E, Lane-Guermonprez L, Arsanto JP, Le Bivic A.
Med Sci (Paris). 2004 Jun-Jul;20(6-7):663-7. PMID: 15329816

PUBLICATION

CRB3 binds directly to Par6 and regulates the morphogenesis of the tight junctions in mammalian epithelial cells.

Lemmers C, Michel D, Lane-Guermonprez L, Delgrossi MH, Médina E, Arsanto JP, Le Bivic A.
Mol Biol Cell. 2004 Mar;15(3):1324-33. PMID: 14718572

PUBLICATION

The scaffolding domain of caveolin 2 is responsible for its Golgi localization in Caco-2 cells.

Breuza L, Corby S, Arsanto JP, Delgrossi MH, Scheiffele P, Le Bivic A.
J Cell Sci. 2002 Dec 1;115(Pt 23):4457-67. PMID: 12414992

PUBLICATION

Role of the Crumbs complex in the regulation of junction formation in Drosophila and mammalian epithelial cells.

Médina E, Lemmers C, Lane-Guermonprez L, Le Bivic A.
Biol Cell. 2002 Oct;94(6):305-13. PMID: 12500938

PUBLICATION

Crumbs interacts with moesin and beta(Heavy)-spectrin in the apical membrane skeleton of Drosophila.

Médina E, Williams J, Klipfell E, Zarnescu D, Thomas G, Le Bivic A.
J Cell Biol. 2002 Sep 2;158(5):941-51. PMID: 12213838

PUBLICATION

hINADl/PATJ, a homolog of discs lost, interacts with crumbs and localizes to tight junctions in human epithelial cells.

Lemmers C, Médina E, Delgrossi MH, Michel D, Arsanto JP, Le Bivic A.
J Biol Chem. 2002 Jul 12;277(28):25408-15. PMID: 11964389

PUBLICATION

Role of the membrane-proximal O-glycosylation site in sorting of the human receptor for neurotrophins to the apical membrane of MDCK cells.

Breuza L, Garcia M, Delgrossi MH, Le Bivic A.
Exp Cell Res. 2002 Feb 15;273(2):178-86. PMID: 11822873
Other publications

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

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

PUBLICATION

PALS1 is essential for retinal pigment epithelium structure and neural retina stratification.

Park B, Alves CH, Lundvig DM, Tanimoto N, Beck SC, Huber G, Richard F, Klooster J, Andlauer TF, Swindell EC, Jamrich M, Le Bivic A, Seeliger MW,Wijnholds J.
J Neurosci. 2011 Nov 23;31(47):17230-41. PMID: 22114289

PUBLICATION

Nephrocystin-1 and nephrocystin-4 are required for epithelial morphogenesis and associate with PALS1/PATJ and Par6.

Delous M, Hellman NE, Gaudé HM, Silbermann F, Le Bivic A, Salomon R, Antignac C, Saunier S.
Hum Mol Genet. 2009 Dec 15;18(24):4711-23. PMID: 19755384

PUBLICATION

CD146 and its soluble form regulate monocyte transendothelial migration.

Bardin N, Blot-Chabaud M, Despoix N, Kebir A, Harhouri K, Arsanto JP, Espinosa L, Perrin P, Robert S, Vely F, Sabatier F, Le Bivic A, Kaplanski G, Sampol J, Dignat-George F.
Arterioscler Thromb Vasc Biol. 2009 May;29(5):746-53. PMID: 19229070

PUBLICATION

FERM protein EPB41L5 is a novel member of the mammalian CRB-MPP5 polarity complex.

Gosens I, Sessa A, den Hollander AI, Letteboer SJ, Belloni V, Arends ML, Le Bivic A, Cremers FP, Broccoli V, Roepman R.
Exp Cell Res. 2007 Nov 15;313(19):3959-70. PMID: 17920587

PUBLICATION

Distinct v-SNAREs regulate direct and indirect apical delivery in polarized epithelial cells.

Pocard T, Le Bivic A, Galli T, Zurzolo C.
J Cell Sci. 2007 Sep 15;120(Pt 18):3309-20. PMID: 17878240

PUBLICATION

Role of aPKC isoforms and their binding partners Par3 and Par6 in epidermal barrier formation.

Helfrich I, Schmitz A, Zigrino P, Michels C, Haase I, le Bivic A, Leitges M, Niessen CM.
J Invest Dermatol. 2007 Apr;127(4):782-91. PMID: 17110935

PUBLICATION

Apical sorting by galectin-3-dependent glycoprotein clustering.

Delacour D, Greb C, Koch A, Salomonsson E, Leffler H, Le Bivic A, Jacob R.
Traffic. 2007 Apr;8(4):379-88. PMID: 17319896

PUBLICATION

Heterogeneity of Raft-type membrane microdomains associated with VP4, the rotavirus spike protein, in Caco-2 and MA 104 cells.

Delmas O, Breton M, Sapin C, Le Bivic A, Colard O, Trugnan G.
J Virol. 2007 Feb;81(4):1610-8. PMID: 17135322

PUBLICATION

Pals1/Mpp5 is required for correct localization of Crb1 at the subapical region in polarized Muller glia cells.

van Rossum AG, Aartsen WM, Meuleman J, Klooster J, Malysheva A, Versteeg I, Arsanto JP, Le Bivic A, Wijnholds J.
Hum Mol Genet. 2006 Sep 15;15(18):2659-72. PMID: 16885194

PUBLICATION

Computer modelling in combination with in vitro studies reveals similar binding affinities of Drosophila Crumbs for the PDZ domains of Stardust and DmPar-6.

Kempkens O, Médina E, Fernandez-Ballester G, Ozüyaman S, Le Bivic A, Serrano L, Knust E.
Eur J Cell Biol. 2006 Aug;85(8):753-67. PMID: 16697075

PUBLICATION

Requirement for galectin-3 in apical protein sorting.

Delacour D, Cramm-Behrens CI, Drobecq H, Le Bivic A, Naim HY, Jacob R.
Curr Biol. 2006 Feb 21;16(4):408-14. PMID: 16488876

PUBLICATION

Junctional recruitment of mammalian Scribble relies on E-cadherin engagement.

Navarro C, Nola S, Audebert S, Santoni MJ, Arsanto JP, Ginestier C, Marchetto S, Jacquemier J, Isnardon D, Le Bivic A, Birnbaum D, Borg JP.
Oncogene. 2005 Jun 23;24(27):4330-9. PMID: 15806148

PUBLICATION

Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells.

Delacour D, Gouyer V, Zanetta JP, Drobecq H, Leteurtre E, Grard G, Moreau-Hannedouche O, Maes E, Pons A, André S, Le Bivic A, Gabius HJ, Manninen A, Simons K, Huet G.
J Cell Biol. 2005 May 9;169(3):491-501. PMID: 15883199

PUBLICATION

Crumbs homologue 1 is required for maintenance of photoreceptor cell polarization and adhesion during light exposure.

van de Pavert SA, Kantardzhieva A, Malysheva A, Meuleman J, Versteeg I, Levelt C, Klooster J, Geiger S, Seeliger MW, Rashbass P, Le Bivic A, Wijnholds J.
J Cell Sci. 2004 Aug 15;117(Pt 18):4169-77. PMID: 15316081

PUBLICATION

Epithelial trafficking: new routes to familiar places.

Rodriguez-Boulan E, Müsch A, Le Bivic A.
Curr Opin Cell Biol. 2004 Aug;16(4):436-42. PMID: 15261677

PUBLICATION

EFA6, exchange factor for ARF6, regulates the actin cytoskeleton and associated tight junction in response to E-cadherin engagement.

Luton F, Klein S, Chauvin JP, Le Bivic A, Bourgoin S, Franco M, Chardin P.
Mol Biol Cell. 2004 Mar;15(3):1134-45. PMID: 14668475

PUBLICATION

Differential recognition of a tyrosine-dependent signal in the basolateral and endocytic pathways of thyroid epithelial cells.

Lipardi C, Ruggiano G, Perrone L, Paladino S, Monlauzeur L, Nitsch L, Le Bivic A, Zurzolo C.
Endocrinology. 2002 Apr;143(4):1291-301. PMID: 11897685

PUBLICATION

Interaction between Erbin and a Catenin-related protein in epithelial cells.

Jaulin-Bastard F, Arsanto JP, Le Bivic A, Navarro C, Vély F, Saito H, Marchetto S, Hatzfeld M, Santoni MJ, Birnbaum D, Borg JP.
J Biol Chem. 2002 Jan 25;277(4):2869-75. PMID: 11711544

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)
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 Veronika Aksenova Magali Barthelemy Elsa Bazellieres Céline Burckle Dominique Massey Harroche Juliette Raitiere Christopher Toret
André Le Bivic
Close window
André Le Bivic

Researcher

Benoît Aigouy
Close window
Benoît Aigouy

Researcher

Veronika Aksenova
Close window
Veronika Aksenova

PhD student

Magali Barthelemy
Close window
Magali Barthelemy

Technical staff

Elsa Bazellieres
Close window
Elsa Bazellieres

Researcher

Céline Burckle
Close window
Céline Burckle

University lecturer

Dominique Massey Harroche
Close window
Dominique Massey Harroche

Researcher

Juliette Raitiere
Close window
Juliette Raitiere

Technical staff

Christopher Toret
Close window
Christopher Toret

Researcher

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