Morphogenesis: cellular mechanisms that control cell-cell adhesion and cell migration during Xenopus laevis gastrulation
A fundamental property of animal and human cells is their ability to adhere to each other, which allows them to assemble into tissues and organs. The assembly of these multicellular structures during embryo development involves highly dynamic changes in cell-cell adhesion and cell migration that appear to rely on remodelling of the actin cytoskeleton and of its links with adhesion molecules. Our goal is to understand the cellular and molecular mechanisms underlying such remodelling events. We also study cell surface receptors that modulate cell adhesion and migration in response to direct contact with adjacent cells. We address these questions with a combination of live imaging, molecular biology, biochemical, biophysical and functional assays, as well as computer modelling.
1) The answer to an old question: how are cells “sorted” to form separate tissues?
In recent years we have studied the formation of embryonic boundaries that delimit the newly formed tissues and prevent them to mix. This phenomenon, which is absolutely essential for proper development, was discovered almost a century ago, but until recently its cellular and molecular bases have remained unclear and highly controversial.
We found that this delimitation process largely relies on repulsive surface cues. Multiple members of the ephrin (Eph) and Eph receptor families act as a “tissue identity codes” that trigger local repulsive reactions at contacts between cells of two different types (for example, ectoderm and mesoderm, or later during gastrulation between dorsal axial and paraxial mesoderm).
2) Intercellular migration
Unlike single-cell migration on an extracellular matrix, cell migration within a tissue is poorly understood. We want to determine how cell-cell adhesion structures are dynamically remodelled during cell migration. We also investigate the regulatory mechanisms that regulate high or low cell motility within different tissues, particularly during gastrulation.
3) EpCAM, a pro-adhesive and pro-migratory cell-cell contact receptor
EpCAM is a tumour-associated protein and a well-known malignancy marker in carcinoma. It was long believed to be an adhesion molecule, but we have discovered that it controls cell adhesion and migration by an unconventional mechanism: it binds directly to and inhibits kinases of the protein kinase C (PKC) family that indirectly regulate contractility of cortical actomyosin. Further studies on EpCAM function and regulation will have a major impact on our understanding of its role in morphogenesis, tissue homeostasis, cancer development and metastasis formation.
ANR Inter-s-cal (François Fagotto)
An EpCAM/Trop2 mechanostat differentially regulates individual and collective migration of human carcinoma cells.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
Cell adhesion and migration in embryonic development
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