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Title: A signaling mechanism coupling netrin-1/deleted in colorectal cancer chemoattraction to SNARE-mediated exocytosis in axonal growth cones
Author: Cotrufo, Tiziana
Pérez-Brangulí, F.
Muhaisen, A.
Ros, O.
Andrés, R.
Baeriswyl, T.
Fuschini, G.
Tarragó Clua, Maria Teresa
Pascual Sánchez, Marta
Ureña Bares, Jesús Mariano
Blasi Cabús, Joan
Giralt Lledó, Ernest
Stoeckli, E.T.
Soriano García, Eduardo
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 12-Oct-2011
Abstract: Directed cell migration and axonal guidance are essential steps in neural development. Both processes are controlled by specific guidance cues that activate the signaling cascades that ultimately control cytoskeletal dynamics. Another essential step in migration and axonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptors and membrane exocytosis are not understood. Netrin-1 is a chemoattractive cue required for the formation of commissural pathways. Here, we show that the Netrin-1 receptor deleted in colorectal cancer (DCC) forms a protein complex with the t-SNARE (target SNARE) protein Syntaxin-1 (Sytx1). This interaction is Netrin-1 dependent both in vitro and in vivo, and requires specific Sytx1 and DCC domains. Blockade of Sytx1 function by using botulinum toxins abolished Netrin-1-dependent chemoattraction of axons in mouse neuronal cultures. Similar loss-of-function experiments in the chicken spinal cord in vivo using dominant-negative Sytx1 constructs or RNAi led to defects in commissural axon pathfinding reminiscent to those described in Netrin-1 and DCC loss-of-function models. We also show that Netrin-1 elicits exocytosis at growth cones in a Sytx1-dependent manner. Moreover, we demonstrate that the Sytx1/DCC complex associates with the v-SNARE (vesicle SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) and that knockdown of TI-VAMP in the commissural pathway in the spinal cord results in aberrant axonal guidance phenotypes. Our data provide evidence of a new signaling mechanism that couples chemotropic Netrin-1/DCC axonal guidance and Sytx1/TI-VAMP SNARE proteins regulating membrane turnover and exocytosis.
Note: Reproducció del document publicat a:
It is part of: Journal of Neuroscience, 2011, vol. 31, num. 41, p. 14463-14480
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ISSN: 0270-6474
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)
Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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