Signalling and cytoskeleton dynamics

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SUMMARY:

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.

MAIN QUESTIONS:

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.

Contact our team

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Anne DEBANT Directrice

Anne Debant

Members of the team

  • Marion BONHOMME
    (Trainee) +33 (0)4 34 35 95 16
  • Maxime BONNET
    (PhD Student) +33 (0)4 34 35 95 16
  • Jerome BOUDEAU
    (Staff Scientist) +33 (0)4 34 35 95 16
  • Anne DEBANT Director & Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 77
  • Christine FAGOTTO-KAUFMANN
    (Research Assistant) +33 (0)4 34 35 95 16
  • Carlos SANCHEZ
    (Post-Doc) +33 (0)4 34 35 95 15
  • Susanne SCHMIDT
    (Staff Scientist) +33 (0)4 34 35 95 16
    • 2018

      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. 8(1):1410. Pubmed

    • 2017

      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[...]

      Clin Cancer Res. 23:857-867. Pubmed

    • 2016

      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;[...]

      J Med Genet. 2016-103942. Pubmed

    • 2015

      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,[...]

      Mol Biol Cell. 26:2112-27. Pubmed

    • 2015

      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. 210:817-32. Pubmed

    • 2015

      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[...]

      Springerplus. 4:528. Pubmed

    • 2014

      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[...]

      Curr Biol. 24:1778-85 Pubmed

    • 2014

      Function and regulation of the Rho guanine nucleotide exchange factor Trio.

      Schmidt S, Debant A.

      Small GTPases. 5:e29769. Pubmed

    • 2014

      Identification of a mitotic Rac-GEF, Trio, that counteracts MgcRacGAP function during cytokinesis.

      Cannet A, Schmidt S, Delaval B, Debant A.

      Mol Biol Cell. 25:4063-71. Pubmed

    • 2013

      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,[...]

      Mol Cell. 49(1):94-108. Pubmed

    • 2013

      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. 33(4):739-51. Pubmed

    • 2013

      Aptamer-derived peptide inhibitors of Rho guanine nucleotide exchange factors.

      Schmidt S, Debant A.

      Enzymes. 33 Pt A:147-68. Pubmed

    • 2012

      Random mutagenesis of peptide aptamers as an optimization strategy for inhibitor screening.

      Bouquier N, Fromont S, Debant A, Schmidt S.

      Methods Mol Biol. 928:97-118. Pubmed

    • 2012

      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. 125(Pt 22):5417-27. Pubmed

    • 2011

      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[...]

      Development. 138(23):5177-88. Pubmed

    • 2010

      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. 123(Pt 12):2111-23. Pubmed

    • 2009

      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. 16(4):391-400. Pubmed

    • 2008

      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,[...]

      Mol Cell Biol. 28(7):2314-23. Pubmed