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Thierry Galli"Neurite Growth: role of the TI-VAMP-dependent vesicular trafficking and its interaction with the cytoskeleton."

Abstract :

Identification of TI-VAMP as a key molecule involved in membrane trafficking mediating neurite outgrowth
Identification of the molecules involved in neurite outgrowth is of crucial importance to understand the normal and pathologicaldevelopment of the brain and also to develop new strategies for the repair of axonal branches and connections. Previous work from our group has identified Tetanus neurotoxin (TeNT) Insensitive-Vesicle Associated Membrane Protein (TI-VAMP alsocalled VAMP-7), a clostridial neurotoxin-insensitive v-SNARE (1) product of the Syb-like gene 1, a pseudoautosomal Xinactived gene (2). TI-VAMP defines a novel membrane compartment, which concentrates at the leading edge of growing axons
and dendrites (3). TI-VAMP has the typical structure of SNARE proteins with a carboxy-terminal transmembrane domain, and a cytosolic SNARE motif involved in the formation of SNARE complexes. TI-VAMP has an amino-terminal extension called
Longin domain (4). The Longin domain inhibits the association of TI-VAMP with plasma membrane t-SNAREs (5). Expression of this domain inhibits neuritogenesis in PC12 cells (6) and both axonal and dendritic outgrowths in neurons (7). In contrast,
expression of the Longin deletion mutant of TI-VAMP increases SNARE complex formation and strongly stimulates neuritogenesis (6, 7). These results points to the Longin domain as a key regulator of neuritogenesis. Furthermore, using knock down by RNAi, we found that TI-VAMP is essential for neuritogenesis and the expression of L1-CAM at the cell surface in cultured neurons (8).

Regulation of TI-VAMP: role of Cdc42, Varp and Rab21 and potential role of Kif5A
The precise regulation of TI-VAMP trafficking and exocytosis, sorting, and transport are largely unknown. We have shown that the TI-VAMP vesicles concentrate at the edge of neuronal growth cones (3) in regions where actin microfilaments concentrate.
Actin cytoskeleton dynamics, a target of GTPases of the RhoA family regulates neurite growth (9, 10). We found that theconcentration of the TI-VAMP vesicles in the F-actin rich region of neuronal growth cones and TI-VAMP-mediated exocytosis depend on actin dynamics and the GTPase Cdc42 but not Rac1 nor RhoA (11). Thus actin dynamics and TI-VAMP-mediated exocytosis are functionally connected in neurite growth and neuronal differentiation. Furthermore, we have recently found that the
Rab21 exchange factor Varp interacts with TI-VAMP and that Rab21 controls the motility and directionality of TI-VAMP on microtubules in growing neurites (12). Varp was recently shown to be a GEF for Rab21 (13) a small GTPase which regulates phagocytosis (14) and cell adhesion by controlling the endosomal trafficking of β1-integrins (15). Furthermore, we have identified putative partners of Varp and effectors of Rab21 and they include several proteins interacting with microtubules. In particular, Varp binds to Kif5A (SPG10) in the dimerisation domain of the kinesin heavy chain. These results indicate strong functional
links between TI-VAMP, actin, and microtubules, three basic components of neurite outgrowth.

Selected publications

Chaineau M, Danglot L, Proux-Gillardeaux V, Galli T (2008) Role of Hrb in clathrin dependent endocytosis. J Biol Chem 283(49):34365-73.

Laroche F., N. Ramoz, S. Leroy, C. Fortin, B. Rousselot-Paillet, A. Philippe, L. Colleaux, B. Golse, M.-C. Mouren-Simeoni, P. Gorwood, T. Galli, M. Simonneau, M.-O. Krebs, and L. Robel.
Polymorphism of coding trinucleotide repeats of Homeogenes in neurodevelopmental psychiatric disorders. Psychiatric Genetics 18(6):295-301.

Sikorra S, Henke T, Galli T, Binz T (2008) Substrate Recognition Mechanism of VAMP/Synaptobrevin-cleaving Clostridial Neurotoxins. J Biol Chem 283: 21145-21152.

Martineau M, Galli T, Baux G, Mothet JP (2008) Confocal imaging and tracking of the exocytotic routes for D-serine-mediated gliotransmission. Glia 56: 1271-1284.