Morphogenesis and Molecular Genetics
The ontogenesis of the neural crest cells is a key morphogenetic process during early embryogenesis that gives rise to numerous derivatives of the body including the enteric nervous system and melanocytes. Alterations affecting the neural crest cells and their derivatives produce several congenital defects, collectively named neurocristopathies, and also cancers. Our team develops multidisciplinary research program, integrating molecular genetics, functional genomics, cell and developmental biology, and mechano-biology with the aim of improving our knowledge of the molecular and cellular bases of neural crest development in normal and pathological conditions with a particular focus on the Waardenburg syndrome (WS), the Hirschsprung disease (HSCR), and DiGeorge-délétion 22q11.
Our team also develop a complementary research axis aiming at characterizing and modelling the cell sensitivity to the mechanical and adhesive properties of the substrates. Mechanical properties of cells, governed mainly by the cytoskeleton organization, together with those of their microenvironment play a major role in integrity and function of tissues. Transmission of mechanical forces between cells and microenvironment depends on mechanoreceptor function and downstream signalling pathways, and allows cells to adapt their behaviour to the viscoelasticity of tissues/biomaterials, thereby controlling numerous processes such as migration, adhesion and differentiation. Nowadays, tissue viscoelasticity becomes a valuable diagnostic biomarker for tissue health, and can be used to orient the development of cellular therapies. Our experimental expertise covers diverse fields including Atomic Force Microscopy in liquid media for structural, mechanical and adhesion assessment on living cells, substrate functionalization using micropatterning techniques, and 3D cell imaging. The cellular response to mechanical and adhesive properties of substrate is modelled by rheological models, mechanical model based on linear and non-linear elasticity theory and stochastic model.
Our main recent research achievements are the following:
– Identification of new mutations within 7 genes involved in WS and MWS, of the 1st deletion of SOX10 regulatory sequences, and of underlying mechanism and functional consequences.
– Characterization and in depth analysis of the interactions between WS, MWS genes and other factors during mouse enteric nervous system development, especially that of Sox10 with Zeb2 or β1-integrins.
– Characterization of the role of β1-integrins during enteric nervous system development, and their crosstalk with N-cadherin and endothelin-3 in vivo during this process as well as in the regulation of cell adhesiveness, traction force and mechanosensing, in vitro.
– Demonstration that SDF1/CXCR4 signalling pathway regulates the spatial segregation of cardiac NCC from enteric NCC and their chemotaxis toward the heart.
– We have demonstrated the importance of the coupling between adhesiveness and cellular mechanics both in vitro and ex vivo, and the role played by specific molecular effectors in the mechano-sensitivity of adhesive contacts.
– We have characterized the mechanical properties of the embryonic intestine and its impact on the enteric neural crest cell migration.
Key words: Neural crest, development, adhesion, migration, pathologies, biomechanics, transcription factors.
Gazquez E, Watanabe Y, Broders-Bondon F, Paul-Gilloteaux P, Heysch J, Baral V, Bondurand N, Dufour S. Endothelin-3 stimulates cell adhesion and cooperates with β1-integrins during enteric nervous system ontogenesis.Sci. Rep. 2016;6:37877.
Broders-Bondon F, Paul-Gilloteaux P, Gazquez E, Heysch J, Piel M, Mayor R, Lambris JD, Dufour S. Control of the collective migration of enteric neural crest cells by the complement anaphylatoxin C3a and N-cadherin.Dev Biol. 2016;414:85-99.
Chevalier NR, Gazquez E, Bidault L, Guilbert T, Vias C, Vian E, Watanabe Y, Muller L, Germain S, Bondurand N, Dufour S, Fleury V. How Tissue Mechanical Properties Affect Enteric Neural Crest Cell Migration.Sci Rep. 2016;6:20927.
Escot S, Blavet C, Faure E, Zaffran S, Duband JL, Fournier-Thibault C.
Disruption of CXCR4 signaling in pharyngeal neural crest cells causes DiGeorge syndrome-like malformations.
Fleury, V., N.R. Chevalier, F. Furfaro, and J.-L. Duband. Buckling along boundaries of elastic contrast as a mechanism for early vertebrate morphogenesis.Eur Phys J E Soft Matter. 2015 Feb;38(2):92.
Duband, J.-L., A. Dady, and V. Fleury. Resolving time and space constraints during neural crest formation and delamination.Curr Top Dev Biol. 2015;111:27-67.
Lecerf, L., A. Kavo, M. Ruiz-Ferrer, V. Baral, Y. Watanabe, A. Chaoui, V. Pingault, S. Borrego, and N. Bondurand.An impairment of long distance SOX10 regulatory elements underlies isolated Hirschsprung disease.Hum Mutat. 2014 Mar;35(3):303-7.
Dady, A., E. Havis, V. Escriou, M. Catala, and J.-L. Duband. Junctional neurulation: a unique developmental program shaping a discrete region of the spinal cord highly susceptible to neural tube defects.J Neurosci. 2014 Sep 24;34(39):13208-21.
von Boxberg Y-V., Soares S., Féréol S,, Fodil R., Bartolami S., Taxi J., Tricaud N, and Nothias F. Giant scaffolding protein AHNAK1 interacts with β-dystroglycan and controls motility and mechanical properties of schwann cells.Glia. 2014 Sep;62(9):1392-406.
Watanabe, Y., F. Broders-Bondon, V. Baral, P. Paul-Gilloteaux, V. Pingault, S. Dufour, and N. Bondurand. Sox10 and Itgb1 interaction in enteric neural crest cell migration.Dev Biol. 2013 Jul 1;379(1):92-106.
Thomas, W.A., C. Boscher, Y.S. Chu, D. Cuvelier, C. Martinez-Rico, R. Seddiki, J. Heysch, B. Ladoux, J.P. Thiery, R.M. Mege, and S. Dufour. alpha-Catenin and vinculin cooperate to promote high E-cadherin-based adhesion strength.J Biol Chem. 2013 Feb 15;288(7):4957-69.
Escot, S., C. Blavet, S. Hartle, J.-L. Duband, and C. Fournier-Thibault. Misregulation of SDF1-CXCR4 signaling impairs early cardiac neural crest cell migration leading to conotruncal defects.Circ Res. 2013 Aug 16;113(5):505-16.
Jasaitis, A., M. Estevez, J. Heysch, B. Ladoux, and S. Dufour. E-cadherin-dependent stimulation of traction force at focal adhesions via the Src and PI3K signaling pathways.Biophys J. 2012 Jul 18;103(2):175-84.
Thiery, J.P., W. Engl, V. Viasnoff, and S. Dufour. Biochemical and biophysical origins of cadherin selectivity and adhesion strength.Curr Opin Cell Biol. 2012 Oct;24(5):614-9.
Broders-Bondon, F., P. Paul-Gilloteaux, C. Carlier, G.L. Radice, and S. Dufour. N-cadherin and beta1-integrins cooperate during the development of the enteric nervous system.Dev Biol. 2012 Apr 15;364(2):178-91.
IMRB – Inserm U955
Morphogenesis and Molecular Genetics (Team 6)
Building R – Entresol 1
Hôpital Henri Mondor
51, avenue du Maréchal De Lattre de Tassigny
Administrative assistant – Contact
Tél. : +33-1 49 81 36 93
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