CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

Elife. 2016 Jun 2;5:e16072. doi: 10.7554/eLife.16072.

Abstract

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

Keywords: C. elegans; CUGBP; DRG; PNS regeneration; UNC-75; mouse; neurite outgrowth; neuroscience; post-transcriptional regulation.

Publication types

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

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Axons / physiology*
  • CELF Proteins / genetics
  • CELF Proteins / metabolism*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism
  • Gene Expression Regulation
  • Locomotion
  • Mice
  • Mice, Knockout
  • Mutation
  • Peripheral Nerve Injuries / metabolism
  • Peripheral Nerve Injuries / pathology
  • Protein Isoforms
  • Qa-SNARE Proteins / genetics*
  • Qa-SNARE Proteins / metabolism
  • RNA-Binding Proteins / metabolism
  • Regeneration

Substances

  • CELF Proteins
  • Caenorhabditis elegans Proteins
  • Celf2 protein, mouse
  • Protein Isoforms
  • Qa-SNARE Proteins
  • RNA-Binding Proteins
  • UNC-75 protein, C elegans