Pr François FAGOTTO

BIOGRAPHY

 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 https://orcid.org/0000-0002-1495-2112

MAJOR RESEARCH CONTRIBUTIONS

 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.