Abstract
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.
Highlights
In mature nervous systems axons regenerate poorly after injury, leading to permanent functional deficits
We show that the Exchange Factor for ARF-6 (EFA-6) N-terminal domain interacts with MT associated proteins TAC-1, a member of the transforming acidic coiled-coil (TACC) family, and ZYG-8, an ortholog of doublecortin-like kinase (DCLK)
We further show that injury triggers relocalization of EFA-6 and TAC-1 to sites overlapping with the MT minus end binding protein Patronin/PTRN-1
Summary
In mature nervous systems axons regenerate poorly after injury, leading to permanent functional deficits. Both the nature of the extracellular environment and the intrinsic growth competence of the neuron contribute to the extent of axon regeneration (Case and Tessier-Lavigne, 2005). Loss of function in cell-intrinsic growth inhibitors such as Phosphatase and Tensin homolog, PTEN, and Suppressor Of Cytokine Signaling-3, SOCS3, can dramatically improve axon regrowth even in the inhibitory CNS environment (Park et al, 2008; Sun et al, 2011). Genetic and pharmacological manipulation of cell autonomous signaling pathways can dramatically improve regrowth of severed axons in various injury paradigms (Moore et al, 2009; Hellal et al, 2011; Sengottuvel et al, 2011; Shin et al, 2012; Watkins et al, 2013; Ruschel et al, 2015)
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