Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase.
Axon injury triggers a series of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. In Caenorhabditis elegans the signaling protein Exchange Factor for ARF-6 (EFA-6) is a potent intrinsic inhibitor of axon regrowth. Here we show that axon injury triggers rapid EFA-6-dependent inhibition of axonal microtubule (MT) dynamics, concomitant with relocalization of EFA-6. EFA-6 relocalization and axon regrowth inhibition require a conserved 18-aa motif in its otherwise intrinsically disordered N-terminal domain. The EFA-6 N-terminus binds the MT-associated proteins TAC-1/Transforming-Acidic-Coiled-Coil, and ZYG-8/Doublecortin-Like-Kinase, both of which are required for regenerative growth cone formation, and which act downstream of EFA-6. After injury TAC-1 and EFA-6 transiently relocalize to sites marked by the MT minus end binding protein PTRN-1/Patronin. We propose that EFA-6 acts as a bifunctional injury-responsive regulator of axonal MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after injury.
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.|University of California, San Diego, La Jolla, United States.
Lizhen
L
Chen
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
Marian
M
Chuang
Department of Biology, Utrecht University, Utrecht, Netherlands.
Thijs
T
Koorman
Department of Biology, Utrecht University, Utrecht, Netherlands.
Mike
http://orcid.org/0000-0003-3966-4173
M
Boxem
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.|University of California, San Diego, La Jolla, United States.|Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, United States.
Yishi
Y
Jin
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, United States.
Andrew D
http://orcid.org/0000-0001-5091-0537
AD
Chisholm
D000818:Animals; D001369:Axons / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D012038:Regeneration
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C554747:EFA-6 protein, C elegans; C524441:TAC-1 protein, C elegans; C439929:zyg-8 protein, C elegans
C. elegans; Patronin; axon regeneration; developmental biology; microtubules; neuroscience; stem cells