Presentation/Session Information

Session Information

Session Title: Regeneration and Synaptic Function Session Type: Parallel
Session Location: De Neve Auditorium Session Time: Sat, Jun 27 8:30AM - 11:30AM

Presentation Information

Program Number: 164 Presentation Time: 8:30AM - 8:42AM

Presentation Content

The microtubule dynamics regulator EFA-6 responds to injury and inhibits axon regeneration via TAC-1 and ZYG-8/DCLK.Lizhen Chen 1,2, Marian Chuang 1, Thijs Koorman 3, Mike Boxem 3, Yishi Jin 1,2, Andrew Chisholm 2. 1)University of California, San Diego, La Jolla, CA; 2)Howard Hughes Medical Institute; 3)Department of Biology, Utrecht University, 3584 CH Utrecht, The Netherlands

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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