TRKB–DOCK3 SIGNALING COORDINATES WAVE1-DEPENDENT ACTIN DYNAMICS AND HAUS7-MEDIATED AXON BRANCHING IN THE ADULT CNS

Adult central nervous system (CNS) axons exhibit limited structural plasticity after injury, and the mechanisms by which extracellular neurotrophic signals are translated into cytoskeletal remodeling required for axonal regeneration remain poorly understood. Here, we investigated how brain-derived neurotrophic factor (BDNF)–TrkB–DOCK3 signaling regulates actin and microtubule dynamics to promote structural plasticity in the adult CNS. DOCK3 is a CNS-specific atypical guanine nucleotide exchange factor for Rac1 that facilitates axonal elongation through coordinated regulation of the cytoskeleton. Mechanistically, DOCK3 promotes axonal regeneration via two complementary pathways. First, DOCK3 interacts with WAVE proteins and controls their intracellular localization, thereby enhancing Rac1-dependent, Arp2/3-mediated actin polymerization. Second, DOCK3 suppresses glycogen synthase kinase-3β (GSK-3β) activity, leading to increased CRMP2-mediated microtubule assembly. Both pathways are essential for efficient axon regeneration. We further identified an interaction between DOCK3 and HAUS augmin-like complex subunit 7 (HAUS7), a component of the augmin complex that mediates microtubule branching nucleation and is closely associated with axonal regeneration in vivo. Activation of TrkB signaling induced phosphorylation of DOCK3 at tyrosine 562, resulting in dissociation of HAUS7 from DOCK3 and subsequent promotion of HAUS7-dependent microtubule branching. Consistent with this mechanism, genetic ablation of Haus7 markedly impaired axonal regeneration in adult mice. Collectively, these findings identify TrkB–DOCK3 signaling as a molecular switch that coordinates actin polymerization and microtubule dynamics, including branching, to enable structural plasticity of adult CNS axons.