Tubulin-tyrosine Ligase (TTL)-mediated Increase in Tyrosinated α-Tubulin in Injured Axons Is Required for Retrograde Injury Signaling and Axon Regeneration

Injured peripheral neurons successfully activate a pro-regenerative program to enable axon regeneration and functional recovery. The microtubule-dependent retrograde transport of injury signals from the lesion site in the axon back to the cell soma stimulates the increased growth capacity of injured neurons. However, the mechanisms initiating this retrograde transport remain poorly understood. Here we show that tubulin-tyrosine ligase (TTL) is required to increase the levels of tyrosinated α-tubulin at the axon injury site and plays an important role in injury signaling. Preventing the injury-induced increase in tyrosinated α-tubulin by knocking down TTL impairs retrograde organelle transport and delays activation of the pro-regenerative transcription factor c-Jun. In the absence of TTL, axon regeneration is reduced severely. We propose a model in which TTL increases the levels of tyrosinated α-tubulin locally at the injury site to facilitate the retrograde transport of injury signals that are required to activate a pro-regenerative program. Background: Axon regeneration following nerve injury depends on retrograde injury signals. Results: An increased tyrosinated α-tubulin level at the injury site is required for the retrograde transport of injury signals and timely activation of a pro-regenerative program. Conclusion: An injury-induced increase in tyrosinated α-tubulin is important for axon regeneration. Significance: Deciphering the mechanisms regulating the retrograde transport of injury signals is crucial for our understanding of regenerative mechanisms in peripheral neurons.