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

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 pathological development 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 also called VAMP-7), a clostridial neurotoxin-insensitive v-SNARE (Galli et al., 1998) product of the Syb-like gene 1, a pseudoautosomal X-inactived gene (D'Esposito et al., 1996). TI-VAMP defines a novel membrane compartment, which concentrates at the leading edge of growing axons and dendrites (Coco et al., 1999). 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 (Filippini et al., 2001). The Longin domain inhibits the association of TI-VAMP with plasma membrane t-SNAREs (Martinez-Arca et al., 2003). Expression of this domain inhibits neuritogenesis in PC12 cells (Martinez-Arca et al., 2000) and both axonal and dendritic outgrowths in neurons (Martinez-Arca et al., 2001). In contrast, expression of the Longin deletion mutant of TI-VAMP increases SNARE complex formation and strongly stimulates neuritogenesis (Martinez-Arca et al., 2000; Martinez-Arca et al., 2001). 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 in cultured neurons (Alberts et al., 2003). Accordingly, lack of synaptotagmin7, a partner of TI-VAMP (Rao et al.