The microtubule regulator ringer functions downstream from the RNA repair/splicing pathway to promote axon regeneration

Genes Dev. 2020 Feb 1;34(3-4):194-208. doi: 10.1101/gad.331330.119. Epub 2020 Jan 9.


Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of Xbp1 mRNA under cellular stress. However, the downstream effectors remain unknown. Here, through transcriptome profiling, we show that the tubulin polymerization-promoting protein (TPPP) ringmaker/ringer is dramatically increased in Rtca-deficient Drosophila sensory neurons, which is dependent on Xbp1. Ringer is expressed in sensory neurons before and after injury, and is cell-autonomously required for axon regeneration. While loss of ringer abolishes the regeneration enhancement in Rtca mutants, its overexpression is sufficient to promote regeneration both in the peripheral and central nervous system. Ringer maintains microtubule stability/dynamics with the microtubule-associated protein futsch/MAP1B, which is also required for axon regeneration. Furthermore, ringer lies downstream from and is negatively regulated by the microtubule-associated deacetylase HDAC6, which functions as a regeneration inhibitor. Taken together, our findings suggest that ringer acts as a hub for microtubule regulators that relays cellular status information, such as cellular stress, to the integrity of microtubules in order to instruct neuroregeneration.

Keywords: Drosophila; HDAC6; MAP1B; Rtca; TPPP; axon regeneration; dendritic arborization neuron; futsch; microtubule; ringer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / metabolism*
  • Animals
  • Axons / physiology*
  • Drosophila / physiology*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gene Expression Regulation, Developmental / genetics
  • Hydroxamic Acids / metabolism*
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / genetics
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding
  • RNA Splicing / genetics
  • Regeneration / genetics*
  • Sensory Receptor Cells / physiology


  • Anilides
  • Drosophila Proteins
  • Hydroxamic Acids
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • futsch protein, Drosophila
  • microtubule-associated protein 1B
  • ringer protein, Drosophila
  • tubacin