In a yeast two-hybrid screen, we identified the microtubule-destabilizing protein SCG10 as a potential effector protein of BRI3. The association was verified using GST pull-down, Co-IP, and their perinuclear co-localization. The analysis of in vitro microtubule polymerization/depolymerization showed that the binding of BRI3 to SCG10 effectively blocked the ability of SCG10 to induce microtubule disassembly, as determined by turbidimetric assays. In intact PC12 cells, BRI3 exhibited the ability to stabilize the microtubule network and attenuate the microtubuledestabilizing activity of SCG10. Furthermore, co-expression of BRI3 with SCG10 attenuated SCG10-mediated PC12 cell neurite outgrowth induced by NGF. These results identify a novel connection between a neuron-specific BRI protein and the cytoskeletal network, suggesting possible roles of BRI3 in the process of neuronal differentiation.