A novel Netrin-1-sensitive mechanism promotes local SNARE-mediated exocytosis during axon branching
Author(s)McClain, Leslie Marie; Winkle, Cortney C.; Valtschanoff, Juli G.; Park, Charles S.; Maglione, Christopher; Gupton, Stephanie L.; ... Show more Show less
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Developmental axon branching dramatically increases synaptic capacity and neuronal surface area. Netrin-1 promotes branching and synaptogenesis, but the mechanism by which Netrin-1 stimulates plasma membrane expansion is unknown. We demonstrate that SNARE-mediated exocytosis is a prerequisite for axon branching and identify the E3 ubiquitin ligase TRIM9 as a critical catalytic link between Netrin-1 and exocytic SNARE machinery in murine cortical neurons. TRIM9 ligase activity promotes SNARE-mediated vesicle fusion and axon branching in a Netrin-dependent manner. We identified a direct interaction between TRIM9 and the Netrin-1 receptor DCC as well as a Netrin-1–sensitive interaction between TRIM9 and the SNARE component SNAP25. The interaction with SNAP25 negatively regulates SNARE-mediated exocytosis and axon branching in the absence of Netrin-1. Deletion of TRIM9 elevated exocytosis in vitro and increased axon branching in vitro and in vivo. Our data provide a novel model for the spatial regulation of axon branching by Netrin-1, in which localized plasma membrane expansion occurs via TRIM9-dependent regulation of SNARE-mediated vesicle fusion.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering
Journal of Cell Biology
Rockefeller University Press, The
Winkle, C. C., L. M. McClain, J. G. Valtschanoff, C. S. Park, C. Maglione, and S. L. Gupton. “A Novel Netrin-1-Sensitive Mechanism Promotes Local SNARE-Mediated Exocytosis During Axon Branching.” The Journal of Cell Biology 205, no. 2 (April 28, 2014): 217–232.
Final published version