Axon injury triggers a complex sequence of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. We previously identified EFA-6 as a potent intrinsic inhibitor of axon regrowth in C. elegans (Chen et al. 2011, Neuron). We report that axon injury triggers a rapid and transient relocalization of EFA-6 from the plasma membrane to the cytoskeleton, concomitant with a local downregulation of axonal MT dynamics after injury. Relocalization is modulated by axonal Ca2+ levels and correlates with EFA-6 protein function in microtubule (MT) regulation and axon regeneration. The N-terminus of EFA-6 is predicted to be an intrinsically disordered domain, and mediates the abilioty of EFA-6 to modulate MT dynamics and axon growth and regeneration. A conserved 18-aa motif in the N terminus is required for its injury-induced relocalization and for inhibition of axon regeneration. We show that the EFA-6 N-terminal domain directly interacts with MT associated proteins TAC-1, a member of the TACC (Transforming-Acidic-Coiled-Coil) family, and ZYG-8, an ortholog of Doublecortin-Like Kinase (DCLK). Using conditional alleles and tissue-specific knockout strategies we find that TAC-1 and ZYG-8 are required for initiation of axon regeneration, and that their overexpression can promote regrowth. Furthermore, injury triggers relocalization of EFA-6 and TAC-1 to sites overlapping with the MT minus end binding protein Patronin/PTRN-1. We propose that EFA-6 is a bifunctional injury-responsive regulator of MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after axon injury.
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