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- Title
A Signaling Mechanism Coupling Netrin-1/Deleted in Colorectal Cancer Chemoattraction to SNARE-Mediated Exocytosis in Axonal Growth Cones.
- Authors
Cotrufo, Tiziana; Pérez-Brangulí, Francesc; Muhaisen, Ashraf; Ros, Oriol; Andrés, Rosa; Baeriswyl, Thomas; Fuschini, Giulia; Tarrago, Teresa; Pascual, Marta; Uren"a, Jesús; Blasi, Joan; Giralt, Ernest; Stoeckli, Esther T.; Soriano, Eduardo
- 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 migrationandaxonal guidance is the regulation of plasmalemma turnover and exocytosis in leading edges and growth cones. However, the cross talk mechanisms linking guidance receptorsandmembraneexocytosis 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-offunction 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-1andDCCloss-of-function models.Wealsoshowthat 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-associatedmembraneprotein(TI-VAMP)andthatknockdownofTI-VAMPin thecommissuralpathway 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.
- Subjects
CELL communication; NETRINS; PROTEIN receptors; COLON cancer; AXONS; CELL migration; EXOCYTOSIS; CELL membranes
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 41, p14463
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3018-11.2011