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7- Neuronal Cell Adhesion and Migration

Research Themes

Neural development proceeds through proliferation and migration of neuronal precursors, their organization in layers and nuclei, then their morphological differentiation leading to the wiring of functional structures. Identifying molecular and cellular mechanisms supporting these developmental processes is important for a better understanding of both the normal brain development and the physiopathology of diseases associated to abnormal neuron positioning or wiring.

The general aim of our team is to understand how the coordinated regulation of cell adhesion, actin dynamics and microtubules arrangement contributes to the migration of neuronal cells. On one hand, the group of RM. MEGE is focusing on the role of signaling cascade activated by cadherin engagement on the control of neuronal cell migration and survival; on the other hand the group of C. METIN is studying the cellular and molecular mechanisms controlling the motility and polarization of cortical interneurons migration.

The RM MEGE group is asking how cadherin adhesion receptors can inform cells about their environment and transmit an adhesion signal allowing controlled cell responses in term of migration, differentiation and survival. Thanks to the development of original strategies based on the use of biomimetic adhesive surfaces activating cadherin and mimicking cell contacts in vitro, we have been able to describe the mechanisms and dynamics of cell-cell contact formation and the transduction of signals controlling cytoskeleton organization, cell cycle and gene expression. We have shown that the extension of neurites induced by cadherin results from the activation of classical biochemical signaling cascades as well as from the adhesion-triggered anchoring of these adhesion receptors to the actin tread-milling in growth cones allowing the transduction across the membrane of traction forces generated by the acto-myosin system.

We are focusing now on the molecular mechanisms responsible of these biochemical and mechanical signal transductions using various cell biology, cellular imaging and biochemical approaches; as well as the physiological consequences of the transduction of the adhesion signal on the migration and polarization of migrating neuronal precursors (in collaboration with C. METIN).

The C METIN group has characterized the migration cycle of future cortical interneurons born in medial ganglionic eminence (MGE). During migration, these neurons exhibit spectacular morphological transformations illustrated by scheme below. By combining live cell imaging and transmission electronic microscopy, we have shown that the migration cycle of these neurons comprises two alternating phases : a forward movement of the centrosome / Golgi apparatus complex at a distance from the nucleus followed by a translocation of the nucleus toward this complex. Nucleokinesis phases are correlated to specific changes in the branched neuritic arbor. In addition, we have shown that the nuclear translocation toward the centrosome requires acto-myosin (in green on scheme) contractility and that non muscle filaments accumulate behind the nucleus.

Our present studies are aimed at studying the organization of the microtubules array at ultrastructural level and at characterizing its changes during migration. We investigate the mechanisms controlling centrosome positioning in these neurons, and in collaboration with RM Mège, we are studying the role of cadherin mediated adhesion in the migratory behavior of MGE cells. Finally, we are studying how proteins mutated in mental retardation impair signalling pathways involved in MGE cell migration.

Team Members

Group leaders: René-Marc MEGE (DR2, CNRS) & Christine METIN (CR1, INSERM)

Laurence Duchesne, Post-Doc

Camilla Luccardini, Post-Doc

Charlotte Plestant, Graduate Student (UPMC)

Lucie Viou, Graduate Student (UPMC)
Pierre Launay, Research fellow

Recent Publications

2010

- Ladoux B, Anon E, Lambert M, Rabodzey A, Hersen P, Buguin A, Silberzan P, Mège RM. Strength Dependence of Cadherin-Mediated Adhesions. Biophys J. 2010 98:534-542.

- Métin C, Luccardini C. Neuroscience. Ubiquitination inhibits neuronal exit. Science. 2010 330:1754-5. Editorial

2009

- Coureuil M, Mikaty G, Miller F, Lécuyer H, Bernard C, Bourdoulous S, Duménil G, Mège RM, Weksler BB, Romero IA, Couraud PO, Nassif X. Meningococcal type IV pili recruit the polarity complex to cross the brain endothelium.Science. 2009 325:83-7.

- Giannone G, Mège RM, Thoumine O. Multi-level molecular clutches in motile cell processes. Trends Cell Biol. 2009 19:475-86. Review.

Selected Publications 2002-2008

2008

Métin C, Vallee RB, Rakic P, Bhide PG. Modes and mishaps of neuronal migration in the mammalian brain. J Neurosci. 2008 Nov 12;28(46):11746-52. Review

Nosten-Bertrand M, Kappeler C, Dinocourt C, Denis C, Germain J, Phan Dinh Tuy F, Verstraeten S, Alvarez C, Métin C, Chelly J, Giros B, Miles R, Depaulis A, and Francis F. Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus. PLoS ONE. 2008 Jun 25;3(6):e2473.

Bard L., Boscher C., Lambert M., Mège R.M., Choquet D. and Thoumine O. A molecular clutch between the actin flow and N-cadherin adhesions drives growth cone migration.J. Neurosci.2008, 28:5879-90.

Boscher C. and Mège RM. Cadherin-11 interacts with the FGF receptor and induces neurites outgrowth through associated downstream pathways. Cell. Signal. 2008, 20: 1061-1072.

2007

Baudoin JP, Alvarez C, Gaspar P and Métin C. Nocodazole induced changes in microtubule dynamics impair the morphology and directionality of migrating MGE cells. Developmental Neurosci. 2008;30(1-3):132-43.

Métin C, Alvarez C, Moudoux D, Vitalis T, PieauC and MolnárZ. Conserved Pattern of Tangential Neuronal Migration During Forebrain Development. Development. 134:2815-27.

Lambert M, Thoumine O, Brévier J, Riveline D, Choquet D and Mège RM. Formation and dynamics of cadherin adhesions. Exp. Cell Res. 2007, 313: 4025-4040.

2006

Ganz A, Lambert M, Saez A, Silberzan P, Buguin A, Mège RM and Ladoux B. Traction forces exerted through N-cadherin contacts. Biol.Cell 98: 721-730.

Guezguez B, Vigneron P, Alais S, Jaffredo T, Gavard J, Mège RM and Dunon D. A dileucine motif targets MCAM-1 cell adhesion molecule to the basolateral membrane in MDCK cells. FEBS Lett. 580: 3649-3656.

Kappeler C, Saillour Y, Baudoin JP, Tuy FP, Alvarez C, Houbron C, Gaspar P, Hamard G, Chelly J, Métin C and Francis F. Branching and nucleokinesis defects in migrating interneurons derived from doublecortin knockout mice. Hum Mol Genet. 15:1387-400.

Thoumine O, Lambert M, Mège RM and Choquet D. Regulation of N-cadherin dynamics at neuronal contacts through ligand binding and cytoskeletal coupling. Mol.Biol.Cell 17: 862-875.

Nicol X, Muzerelle A, Rio JP, Métin C and Gaspar P. Requirement of adenylate cyclase 1 for the ephrin-A5-dependent retraction of exuberant retinal axons. J. Neurosci. 26:862-72.

Mège RM, Gavard J and Lambert M Regulation of cell-cell junctions by the cytoskeleton. Curr.Opin.Cell Biol. (2006) 18:541-548.

Métin C, Baudoin, J-P, Rakic S and Parnavelas J. Cell and molecular mechanisms involved in the migration of cortical interneurons. Eur J Neurosci. (2006) 23: 894-900

Molnar Z, Métin C, Stoykova A, Tarabykin V, Price DJ, Francis F, Meyer G, Dehay C and Kennedy H. Comparative aspects of cerebral cortical development. Eur J Neurosci. (2006) 23: 921-934.

2005

Bellion A and Métin C. Early regionalisation of the neocortex and the medial ganglionic eminence. Brain Res. Bull. 66: 402-9.

Bellion A, Baudoin JP, Alvarez C, Bornens M and Métin C. Nucleokinesis in tangentially migrating neurons comprises two alternating phases: forward migration of the Golgi/centrosome associated with centrosome splitting and myosin contraction at the rear. J. Neurosci. 25:5691-9.

Birbes H, Luberto C, Hsu YT, El Bawab S, Hannun YA and Obeid LM. A Mitochondrial pool of sphingomyelin is involved in TNF{alpha}-induced Bax transloc-ation to mitochondria. Biochem. J. 385: 1-7.

Marthiens V, Gavard J, Padilla F, Monnet C, Castellani V, Lambert M and Mège RM. Functional properties of cadherin-11, a cell adhesion receptor involved in motor axon elongation and fasciculation. Mol. Cell. Neurosci 28: 715-726.

Proux-Gillardeaux V, Gavard J, Irinopoulou T, Mège RM and Galli T. Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrin-dependent cell adhesion. Proc. Natl. Acad. Sci. USA. 102: 6362-6367.

Gavard J and Mège RM. Once upon a time there was b-catenin in cadherin-mediated signalling. Biol. Cell (2005) 97: 921-926.

2004

Gavard J, Lambert M, Grosheva I, Marthiens V, Irinopoulou T, Riou J-F, Bershadsky A and Mège RM. Lamellipodium extension and cadherin adhesion: two cell responses to cadherin activation relying on distinct signalling pathways. J.Cell Sci. 117: 257-270.

Gavard J, Marthiens V, Monnet C, Lambert M. and Mège RM. N-cadherin activation substitutes for the cell control in cell-cycle arrest and myogenic differentiation: involvement of p120 and -catenin. J.Biol.Chem. 279: 36795-36802.

Monnet C, Gavard J, Mège RM and Sobel A. Clustering of cellular prion protein induces ERK1/2 and stathmin phosphorylation in GT1-7 neuronal cells. FEBS Lett. 576: 114-118.

Gavard J, Marthiens V, Monnet C, Boscher C, Lambert M and Mège RM. Regulation of cell adhesion by cadherin cytoplasmic domain. J. Soc. Biol. (2004) 198: 365-374.

2003

Ahrens T, Lambert M, Pertz O, Sasaki T, Schulthess T, Mège RM, Timpl R and Engel J. Homo-association of VE-cadherin follows a mechanism common to "classical' cadherins. J. Mol. Biol. 325: 733-742.

Bellion A, Wassef M, Métin C. Early differences in axonal outgrowth, cell migration and GABAergic differentiation properties between the dorsal and lateral cortex. Cereb. Cortex. 13:203-14.

Jossin Y, Ogawa M, Métin C, Tissir F, Goffinet AM. Inhibition of SRC family kinases and non-classical protein kinases C induce a reeler-like malformation of cortical plate development. J. Neurosci. 23:9953-9959.

Louvi A, Alexandre P, Métin C, Wurst W, Wassef M. The isthmic neuroepithelium is essential for cerebellar midline fusion. Development. 130:5319-30.

Monnet C, Marthiens V, Enslen H, Frobert Y, Sobel A and Mège RM. Heterogeneity and regulation of cellular prion protein glycoforms in neuronal cell lines. Eur. J. Neurosci. 18: 542-548.

2002

Marthiens V, Padilla F, Lambert M and Mège RM. Complementary expression and regulation of cadherins 6 and 11 during specific steps of motoneuron differentiation. Mol. Cell. Neurosci. 20: 458-475.

Lambert M, Choquet D and Mège RM. Dynamics of ligand-induced, Rac-1dependent anchoring of cadherins to the actin cytoskeleton. J. Cell Biol. 157: 469-479.

Coussen F, Normand E, Marchal C, Costet P, Choquet D, Lambert M, Mège RM and Mülle C. Recruitment of kainate receptor subunit glutatame receptor 6 by cadherin/catenin complexes. J. Neurosci. 22: 6426-6436.

Marthiens V, Gavard J, Lambert M and Mège RM. Cadherin-based cell adhesion in neuromuscular development. Biol. Cell (2002) 94: 315-326.

Publié le mardi 24 avril 2012

FLASH

For more see "Publications"

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