Current Biology
Volume 24, Issue 15, 4 August 2014, Pages 1778-1785
Journal home page for Current Biology

Report
Dynamic Microtubules Catalyze Formation of Navigator-TRIO Complexes to Regulate Neurite Extension

https://doi.org/10.1016/j.cub.2014.06.037Get rights and content
Under an Elsevier user license
open archive

Highlights

  • NAV1 interacts and colocalizes with the RhoGEF TRIO

  • NAV1 regulates TRIO-mediated Rac1 activation and neurite outgrowth

  • TRIO is a microtubule plus-end-tracking protein that interacts with EB1

  • EB1-coated microtubules regulate formation and targeting of NAV1-TRIO complexes

Summary

Neurite extension is regulated by multiple signaling cascades that ultimately converge on the actin and microtubule networks [1]. Rho GTPases, molecular switches that oscillate between an inactive, GDP-bound state and an active, GTP-bound state, play a pivotal role in controlling actin cytoskeleton dynamics in the growth cone [2], whereas the dynamic behavior and interactions of microtubules are largely regulated by proteins called plus-end-tracking proteins (+TIPs), which associate with the ends of growing microtubules [3]. Here, we show that the +TIP Navigator 1 (NAV1) is important for neurite outgrowth and interacts and colocalizes with TRIO, a Rho guanine nucleotide exchange factor that enables neurite outgrowth by activating the Rho GTPases Rac1 and RhoG [4, 5]. We find that binding of NAV1 enhances the affinity of TRIO for Rac1 and RhoG, and that NAV1 regulates TRIO-mediated Rac1 activation and neurite outgrowth. TRIO is also a +TIP, as it interacts with the core +TIP EB1 and tracks microtubule plus ends via EB1 and NAV1. Strikingly, the EB1-mediated recruitment of TRIO to microtubule ends is required for proper neurite outgrowth, and stabilization of the microtubule network by paclitaxel affects both the TRIO-NAV1 interaction and the accumulation of these proteins in neurite extensions. We propose that EB1-labeled ends of dynamic microtubules facilitate the formation and localization of functional NAV1-TRIO complexes, which in turn regulate neurite outgrowth by selectively activating Rac1. Our data reveal a novel link between dynamic microtubules, actin cytoskeleton remodeling, and neurite extension.

Cited by (0)

4

Co-first author

5

Present address: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94413, USA