Neuronal connectivity is based on complex developmental processes, such as axon outgrowth and guidance, dendritic arborisation, and synaptogenesis. These processes rely on the coordination of actin cytoskeleton remodelling and microtubule dynamics. Rho GTPases are major players in neuronal morphogenesis because they control actin cytoskeleton remodelling. Our long-term interest is to understand how Rho GTPase signalling controls axon outgrowth and guidance as well as synaptogenesis. Disruption of these processes can lead to neurological diseases, such as schizophrenia, autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, a better knowledge of these molecular mechanisms will improve the understanding and diagnosis of neurological diseases related to defects in these processes.
We use different complementary biochemical and cell biology methods (e.g., live and high resolution fluorescence microscopy) and an integrated approach with transgenic mouse models to address the following questions:
What are the functions of Rho GTPase signalling components in axon outgrowth and in synaptogenesis?
How are these proteins regulated during these developmental processes?
How do these proteins contribute to the coordination between actin cytoskeleton remodelling and microtubule dynamics?
How can the deregulation of Rho GTPase signalling contribute to neurological diseases?
PROJECTS OF THE LABORATORY:
i) Rho GTPase signalling and axon outgrowth
GTPases of the Rho family are molecular switches that are activated by guanine nucleotide exchange factors (GEF) and inactivated by GTPase-activating proteins (GAP). We and others have shown that the Rho GEF Trio is a major regulator of cell migration and axon outgrowth by controlling actin cytoskeleton remodelling through the activation of the Rho GTPase Rac1. We have recently uncovered an unexpected physical link between Trio and proteins involved in the control of microtubule (MT) dynamics, and we have demonstrated that Trio ability to bind to MTs is essential for its function in axon outgrowth. Our current work aims at deciphering the molecular mechanisms underlying the interplay between Trio, actin cytoskeleton remodelling, and MT dynamics during axon outgrowth.
ii) Rho GTPase signalling and synaptogenesis
In addition to axon outgrowth, Rho GTPases also participate in the morphogenesis of dendritic spines that form and establish synaptic contacts during brain development. We have recently identified new members of the Rho GTPase signalling cascade that contribute to the formation of dendritic spines, including the Rho GEF DOCK10. We are now studying the molecular mechanisms by which these proteins control this process. In addition, we are testing whether disruption of the function of these proteins contributes to the development of neuronal disorders.
En savoir plus
ANR HERC2-DOCKD-Modul (Suzanne Schmidt)
ANR TRIOTISM (Anne Debant)
- Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature. Gazdagh G, Hunt D, Gonzalez AMC, Rodriguez MP, Chaudhry A, Madruga M, Vansenne F, Shears D, Curie A, Stattin EL, Anderlid BM, Trajkova S, Angelovska ES, McWilliam C, Wyatt PR, O’Driscoll M, Atton G, Bergman AK, Zacher P, Mewasingh LD, López AG, Alonso-Luengo O, Wai HA, Rohde O, Boiroux P, Debant A, Schmidt S, Baralle D. Am J Med Genet A. 2023 Mar 29. Pubmed
- Pathogenic TRIO variants associated with neurodevelopmental disorders perturb the molecular regulation of TRIO and axon pathfinding in vivo. Bonnet M, Roche F, Fagotto-Kaufmann C, Gazdagh G, Truong I, Comunale F, Barbosa S, Bonhomme M, Nafati N, Hunt D, Rodriguez MP, Chaudhry A, Shears D, Madruga M, Vansenne F, Curie A, Kajava AV, Baralle D, Fassier C, Debant A, Schmidt S. Mol Psychiatry. 2023 Jan 30. Pubmed
- The +TIP Navigator-1 Is an Actin-Microtubule Crosslinker That Regulates Axonal Growth Cone Motility. Carlos Sánchez-Huertas, Marion Bonhomme, Amandine Falco, Christine Fagotto-Kaufmann, Jeffrey van Haren, Freddy Jeanneteau, Niels Galjart, Anne Debant, Jérôme Boudeau. J Cell Biol . 2020 Sep 7;219(9):e201905199. Pubmed
- Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders. Barbosa S, Greville-Heygate S, Bonnet M, Godwin A, Fagotto-Kaufmann C, Kajava AV, Laouteouet D, Mawby R, Wai HA, Dingemans AJM, Hehir-Kwa J, Willems M, Capri Y, Mehta SG, Cox H, Goudie D, Vansenne F, Turnpenny P, Vincent M, Cogné B, Lesca G, Hertecant J, Rodriguez D, Keren B, Burglen L, Gérard M, Putoux A; C4RCD Research Group, Cantagrel V, Siquier-Pernet K, Rio M, Banka S, Sarkar A, Steeves M, Parker M, Clement E, Moutton S, Tran Mau-Them F, Piton A, de Vries BBA, Guille M, Debant A, Schmidt S, Baralle D. Am J Hum Genet. 2020 Mar 5;106(3):338-355. Pubmed
- Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination. Acosta MI, Urbach S, Doye A, Ng YW, Boudeau J, Mettouchi A, Debant A, Manser E, Visvikis O, Lemichez E. Sci Rep. 2018 Jan 23;8(1):1410. Pubmed
- Recurrent TRIO Fusion in Nontranslocation-Related Sarcomas. Delespaul L, Lesluyes T, Pérot G, Brulard C, Lartigue L, Baud J, Lagarde P, Le Guellec S, Neuville A, Terrier P, Vince-Ranchère D, Schmidt S, Debant A, Coindre JM, Chibon F. Clin Cancer Res. 2017 Feb 1;23(3):857-867. Pubmed
- Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. Pengelly RJ, Greville-Heygate S, Schmidt S, Seaby EG, Jabalameli MR, Mehta SG, Parker MJ, Goudie D, Fagotto-Kaufmann C, Mercer C; DDD Study, Debant A, Ennis S, Baralle D. J Med Genet. 2016-103942. Pubmed
- The RhoGEF DOCK10 is essential for dendritic spine morphogenesis. Jaudon F, Raynaud F, Wehrlé R, Bellanger JM, Doulazmi M, Vodjdani G, Gasman S, Fagni L, Dusart I, Debant A, Schmidt S. Mol Biol Cell. 2015 Jun 1;26(11):2112-27. Pubmed
- Hsc70 chaperone activity underlies Trio GEF function in axon growth and guidance induced by netrin-1. DeGeer J, Kaplan A, Mattar P, Morabito M, Stochaj U, Kennedy TE, Debant A, Cayouette M, Fournier AE, Lamarche-Vane N. J Cell Biol. 2015 Aug 31;210(5):817-32. Pubmed
- Comprehensive prognostic analysis in breast cancer integrating clinical, tumoral, micro-environmental and immunohistochemical criteria. de Mascarel I, Debled M, Brouste V, Mauriac L, Sierankowski G, Velasco V, Croce S, Chibon F, Boudeau J, Debant A, MacGrogan G. 2015 Sep 21;4:528. Pubmed
- Dynamic microtubules catalyze formation of navigator-TRIO complexes to regulate neurite extension. van Haren J, Boudeau J, Schmidt S, Basu S, Liu Z, Lammers D, Demmers J, Benhari J, Grosveld F, Debant A, Galjart N. Curr Biol. 2014 Aug 4;24(15):1778-85. Pubmed
- Function and regulation of the Rho guanine nucleotide exchange factor Trio. Schmidt S, Debant A. Small GTPases. 2014;5:e29769. Pubmed
- Identification of a mitotic Rac-GEF, Trio, that counteracts MgcRacGAP function during cytokinesis. Cannet A, Schmidt S, Delaval B, Debant A. Mol Biol Cell. 2014 Dec 15;25(25):4063-71. Pubmed
- A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors. Vaqué JP, Dorsam RT, Feng X, Iglesias-Bartolome R, Forsthoefel DJ, Chen Q, Debant A, Seeger MA, Ksander BR, Teramoto H, Gutkind JS. Mol Cell. 49(1):94-108. Pubmed
- Tyrosine phosphorylation of the Rho guanine nucleotide exchange factor Trio regulates netrin-1/DCC-mediated cortical axon outgrowth. DeGeer J, Boudeau J, Schmidt S, Bedford F, Lamarche-Vane N, Debant A. Mol Cell Biol. 2013 Feb;33(4):739-51. Pubmed
- Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors. Schmidt S, Debant A. Enzymes. 2013;33 Pt A:147-68. Pubmed
- Random mutagenesis of peptide aptamers as an optimization strategy for inhibitor screening. Bouquier N, Fromont S, Debant A, Schmidt S. Methods Mol Biol. 2012;928:97-118. Pubmed
- The doublecortin-related gene zyg-8 is a microtubule organizer in Caenorhabditis elegans neurons. Bellanger JM, Cueva JG, Baran R, Tang G, Goodman MB, Debant A. J Cell Sci. 2012 Nov 15;125(Pt 22):5417-27. Pubmed
- A Trio-RhoA-Shroom3 pathway is required for apical constriction and epithelial invagination. Plageman TF Jr, Chauhan BK, Yang C, Jaudon F, Shang X, Zheng Y, Lou M, Debant A, Hildebrand JD, Lang RA. 2011 Dec;138(23):5177-88. Pubmed
- Kidins220/ARMS regulates Rac1-dependent neurite outgrowth by direct interaction with the RhoGEF Trio. Neubrand VE, Thomas C, Schmidt S, Debant A, Schiavo G. J Cell Sci. 2010 Jun 15;123(Pt 12):2111-23. Pubmed
- Aptamer-derived peptides as potent inhibitors of the oncogenic RhoGEF Tgat. Bouquier N, Fromont S, Zeeh JC, Auziol C, Larrousse P, Robert B, Zeghouf M, Cherfils J, Debant A, Schmidt S. Chem Biol. 2009 Apr 24;16(4):391-400. Pubmed
- Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Briançon-Marjollet A, Ghogha A, Nawabi H, Triki I, Auziol C, Fromont S, Piché C, Enslen H, Chebli K, Cloutier JF, Castellani V, Debant A, Lamarche-Vane N. Mol Cell Biol. 28(7):2314-23. Pubmed
Signalling and cytoskeleton dynamics
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