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Morphogénèse: Mécanismes cellulaires régulateurs de l’adhérence et de la migration cellulaire lors de la gastrulation du Xénope

Une propriété fondamentale des cellules animales et humaines est leur capacité d’adhérer les unes aux autres, ce qui leur permet de s’assembler en tissus et organes. La formation de ces structures multicellulaires durant le développement embryonnaire implique des changements très dynamiques de l’adhérence et de la migration cellulaire, qui semblent dépendre du remodelage du cytosquelette d’actine et ses liens avec les molécules d’adhérence. Notre but est de comprendre ces mécanismes de remodelage et leur régulation. Nous étudions aussi des récepteurs de surface dont la fonction est de moduler l’adhérence et la migration en réponse au contact avec les cellules voisines. Pour cela nous appliquons une approche multidisciplinaire combinant imagerie, biologie moléculaire et biochimie, biophysique, différents tests fonctionnels, et modélisation.

Pr François FAGOTTO


 Of mixed Swiss French and Venetian background, I studied Biology at the University of Neuchâtel, one of the smallest universities in Europe. I stayed there for my PhD, choosing a not-so-common topic, i.e. yolk degradation (embryonic storage) in an exotic model, an African tick. In 1991, I went for a first postdoc at Columbia University, New York City, in the lab of Fred Maxfield, a pioneer of live imaging and of the study of endosomes. There I still fumbled with yolk “late endosomes” and regulation of their pH.

Leaving yolk aside for good, I then crossed Manhattan from the West to the East Side to join the lab of Barry Gumbiner at the Sloan-Kettering Institute, right at the time where the dual role of β-catenin in adhesion and Wnt signalling was being discovered. I explored various facets of this topic, from its role during embryonic development to the mechanism of β-catenin nuclear transport. Toward the end of this second postdoc, in a collaboration with the lab of Frank Constantini, I discovered Axin, the scaffold protein building the β-catenin degradation complex.

In 1997, I started my own team as 5-year junior group leader at the Max-Planck Institute of Developmental Biology in Tübingen, continuing to work on β-catenin and Axin. In 2002, I moved to McGill University, Montreal, where I held a Canada Research Chair. There I fully entered the field of morphogenesis, using the Xenopus gastrula as model to decipher the cellular mechanisms responsible for cell sorting and separation of embryonic tissues.

Pressed by my longing for centennial stone buildings and for alpine pastures, I came back to old Europe in 2015, as Professor at the University of Montpellier and team leader at the CRBM-CNRS Institute. This last move coincided with starting to explore a new aspect of morphogenesis, tackling the basis of tissue motility and remodelling using a combination of cellular and biophysical approaches.

CV and complete list of publications can be found at



 Separate functions of β-catenin in Wnt signaling and cell adhesion

Funayama et al, J. Cell Biol. 1996

β-catenin had just been discovered as central cadherin interactor for cell adhesion, but also as component of the Wnt signalling pathway. We provided the first demonstration that β-catenin localized in the nucleus upon Wnt activation, that signalling and adhesive functions could be dissociated, and that cadherin binding sequestered β-catenin, thus antagonizing Wnt signalling.


Discovery of Axin, the central scaffold protein of the Wnt pathway

Zeng*, Fagotto*, et al. Cell 1997 (* First equal authors)

Despite the knowledge of several components of the pathway, the mechanism regulating b-catenin had remained quite puzzling.  Axin turned out to be a key molecule: it functions as a scaffold protein that can recruit basically all cytoplasmic components of the pathway.  Its discovery provided for the first time a coherent view of the pathway, and gave a strong impulse to the field, allowing the identification of many new interacting partners, and of cross talks with other pathways.


β-catenin nuclear transport

Fagotto et al, Curr. Biol. 1998; Wiechens and Fagotto, Curr. Biol. 2001

We showed that β-catenin can freely shuttle in and out of the nucleus in a very unconventional way, independently of the classical nuclear transport pathways. β-catenin may actually have evolved from an ancestor “importin”, and whether it may have retained a function as nuclear transport receptor is an open question (Fagotto, EMBO Rep. 2013).


The Signaling Atlas of Xenopus Development

Schohl and Fagotto, Development 2002

In this study, we produced an 4D atlas of four major pathways involved in embryonic development, from early blastula stage to hatching. This atlas provided the first global view of the complex sequence of signals involved in the development of an animal organism. It is recognized as a major must-read resource by the Xenopus community.


Embryonic boundaries rely on local cell repulsion

Rohani et al, PLoS Biology 2011

This study provided the first high resolution images of cell behavior at an embryonic boundary. It revealed that ectoderm and mesoderm of the Xenopus gastrula remained separated due to constant cycles of adhesion-deadhesion controlled by ephrin-Eph signaling across the boundary. This work overturned the prevailing models, which postulated that tissue separation relied on global adhesive or contractile differences between the tissues.


Tumor associated EpCAM is a PKC inhibitor that controls cell adhesion and motility.

Maghzal et al, Developmental Cell 2013

EpCAM is a major marker for carcinoma. While it was long thought to function as cell adhesion molecule, we had found that in Xenopus embryos it stimulates cell adhesion and cell migration indirectly by inhibiting PKC signaling (Maghzal et al, J. Cell Biol. 2010). We reported here that EpCAM cytoplasmic tail contains a short peptide segment that directly binds and inhibits intracellular kinases, called novel PKCs. Other proteins involved in adhesion or repulsion also carry a similar PKC-inhibitory domain. We thus uncovered a novel mechanism of intracellular signaling regulation by cell membrane proteins.


Regulation of cadherin adhesion along the embryonic boundary

Fagotto et al, Developmental Cell 2013

Using formation of the notochord in Xenopus, we showed that repulsive cues generate acute actomyosin contractility at the tissue interface, locally inhibiting cadherin clustering, thus explaining the low adhesion across the boundary and high efficiency of cell sorting. This is the first in vivo evidence for regulation of cadherin clustering, a mechanism which may have a broad impact on cell-cell adhesion and morphogenesis.


A “tissue identity code” made of selective ephrin-Eph pairs

Rohani et al, PLoS Biology 2014

We demonstrated that vertebrate embryonic cells recognize self from non-self, thus restricting repulsion at tissue boundaries, through a combination of multiple ephrins and Eph receptors, simply based on binding selectivity and asymmetric expression. This study, dissecting ephrin-Eph networks at three different Xenopus boundaries, provides a molecular mechanism for the “cell affinities” postulated more than seventy years ago to explain how different cell types can sort into separate tissues.


High heterotypic interfacial tension as mechanistic basis of embryonic boundaries.

Canty et al, Nature Comm 2017

Formal, definitive demonstration through experimental data and biophysical modelling that cell sorting and tissue separation cannot be generated by global differences in cell adhesion or contractility, as widely previously assumed, but are instead driven by local high local tension at the interface between the cell types. For reviews on this fundamental concept, see Fagotto, Development 2014, and Fagotto, Sem. Cell Dev. Biol. 2020.


Ectoderm to mesoderm transition by downregulation of actomyosin contractility

Kashkooli, Rozema et al, PLoS BIOLOGY 2021

Discovery that mesoderm migration during gastrulation is triggered by a developmentally-controlled inhibition of the Rho-Rock-myosin pathway, and identification of corresponding tissue-specific Rho inhibitors. This view of collective migration of a mesenchymal-like tissue stimulated by cell “softening” contrasts with the classical model for epithelial morphogenesis, which considers high contractility as the motor of tissue remodelling.

ANR Inter-s-cal (François Fagotto)




  • An EpCAM/Trop2 mechanostat differentially regulates individual and collective migration of human carcinoma cells. Azam Aslemarz, Marie-Fagotto Kaufmann, Artur Ruppel, Martial Balland, Paul Lasko, François Fagotto. Pubmed


  • Ectoderm to mesoderm transition by down-regulation of actomyosin contractility. Kashkooli L, Rozema D, Espejo-Ramirez L, Lasko P, Fagotto F. PLoS Biol. 2021 Jan 6;19(1):e3001060 Pubmed
  • EpCAM cellular functions in adhesion and migration, and potential impact on invasion: A critical review. François Fagotto , Azam Aslemarz. Biochim Biophys Acta Rev Cancer, 2020 Dec;1874(2):188436. Pubmed
  • Tissue segregation in the early vertebrate embryo. François Fagotto. Semin Cell Dev Biol. 2020 Nov;107:130-146. Pubmed
  • Cell sorting at embryonic boundaries. François Fagotto. Semin in Cell Dev Biol. 2020 Nov;107:126-129. Pubmed
  • EpCAM as Modulator of Tissue Plasticity. François Fagotto. Cells; 2020 Sep 19;9(9):2128. Pubmed


  • Limited significance of the in situ proximity ligation assay. Azam Alsemarz, Paul Lasko, François Fagotto. bioRxiv 411355 (November 05, 2018) Pubmed


  • Sorting at embryonic boundaries requires high heterotypic interfacial tension. Canty L, Zarour E, Kashkooli L, François P, Fagotto F. Nat Commun. 2017 Jul 31;8(1):157. Pubmed


  • Regulation of cell adhesion and cell sorting at embryonic boundaries. Fagotto F. Curr Top Dev Biol. 2015;112:19-64. Pubmed
  • Nuclear β-Catenin under Control. Fagotto F. Dev Cell. 2015 Jun 22;33(6):625-6. Pubmed


  • Regulation of the phosphorylation and nuclear import and export of β-catenin by APC and its cancer-related truncated form. Wang L, Liu X, Gusev E, Wang C, Fagotto F. J Cell Sci. 2014 Apr 15;127(Pt 8):1647-59. Pubmed
  • Variable combinations of specific ephrin ligand/Eph receptor pairs control embryonic tissue separation. Rohani N, Parmeggiani A, Winklbauer R, Fagotto F. PLoS Biol. 2014 Sep 23;12(9):e1001955. Pubmed
  • The cellular basis of tissue separation. Fagotto F. Development. 2014 Sep;141(17):3303-18. Pubmed
  • Ephrin-Eph signaling in embryonic tissue separation. Fagotto F, Winklbauer R, Rohani N. Cell Adh Migr. 2014;8(4):308-26. . Pubmed


  • Looking beyond the Wnt pathway for the deep nature of β-catenin. Fagotto F. EMBO Rep. 2013 May;14(5):422-33. Pubmed
  • A molecular base for cell sorting at embryonic boundaries: contact inhibition of cadherin adhesion by ephrin/ Eph-dependent contractility. Fagotto F, Rohani N, Touret AS, Li R. Dev Cell. 2013 Oct 14;27(1):72-87. Pubmed
  • EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F. Dev Cell. 2013 Nov 11;27(3):263-77. Pubmed


  • Cadherin-dependent differential cell adhesion in Xenopus causes cell sorting in vitro but not in the embryo. Ninomiya H, David R, Damm EW, Fagotto F, Niessen CM, Winklbauer R. J Cell Sci. 2012 Apr 15;125(Pt 8):1877-83. Pubmed
  • Maternal Wnt/β-catenin signaling coactivates transcription through NF-κB binding sites during Xenopus axis formation. Armstrong NJ, Fagotto F, Prothmann C, Rupp RA. PLoS One. 2012;7(5):e36136. Pubmed
  • Polyvalent DP1 keeps the Wnt pathway neat and tidy. Fagotto F. EMBO J. 2012 Aug 15;31(16):3377-9. Pubmed
  • Proteomic analysis of differences in ectoderm and mesoderm membranes by DiGE. Wang R, Liu X, Küster-Schöck E, Fagotto F. J Proteome Res. 2012 Sep 7;11(9):4575-93. Pubmed


  • EphrinB/EphB signaling controls embryonic germ layer separation by contact-induced cell detachment. Rohani N, Canty L, Luu O, Fagotto F, Winklbauer R. PLoS Biol. 2011 Mar;9(3):e1000597. Pubmed
  • A method to separate nuclear, cytosolic, and membrane-associated signaling molecules in cultured cells. Liu X, Fagotto F. Sci Signal. 2011 Dec 13;4(203):pl2. Pubmed


  • The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. Maghzal N, Vogt E, Reintsch W, Fraser JS, Fagotto F. J Cell Biol. 2010 Nov 1;191(3):645-59. Pubmed


  • Selective pharmacological targeting of a DEAD box RNA helicase. Lindqvist L, Oberer M, Reibarkh M, Cencic R, Bordeleau ME, Vogt E, Marintchev A, Tanaka J, Fagotto F, Altmann M, Wagner G, Pelletier J. PLoS One. 2008 Feb 13;3(2):e1583. Pubmed
  • Plasma membrane recruitment of dephosphorylated beta-catenin upon activation of the Wnt pathway. Hendriksen J, Jansen M, Brown CM, van der Velde H, van Ham M, Galjart N, Offerhaus GJ, Fagotto F, Fornerod M. J Cell Sci. 2008 Jun 1;121(11):1793-802. Pubmed
  • Inhibition of cell adhesion by xARVCF indicates a regulatory function at the plasma membrane. Reintsch WE, Mandato CA, McCrea PD, Fagotto F. Dev Dyn. 2008 Sep;237(9):2328-41. Pubmed
  • Detection of nuclear beta-catenin in Xenopus embryos. Fagotto F, Brown CM. Methods Mol Biol. 2008;469:363-80. Pubmed

Adhérence et migration cellulaire dans le développement embryonnaire

François FAGOTTO

Chef d’équipe (Professeur)

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    Highly migratory cells isolated from Xenopus embryos can be studied in vitro

    Lower caption:
    Left: High resolution live confocal microscopy of mesoderm cells plated on fibronectin
    Right: Segmentation of the same cells, highlighting the highly dynamic extending and retracting protrusions



    Ectoderm to mesoderm transition by down-regulation of actomyosin contractility.

    Kashkooli L, Rozema D, Espejo-Ramirez L, Lasko P, Fagotto F.

    PLoS Biol. 2021 Jan 6;19(1):e3001060.


    EpCAM cellular functions in adhesion and migration, and potential impact on invasion: A critical review.

    Fagotto F, Aslemarz A.

    Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188436.


    Sorting at embryonic boundaries requires high heterotypic interfacial tension.

    Canty L, Zarour E, Kashkooli L, François P, Fagotto F.

    Nat Commun. 2017 Jul 31;8(1):157.