Axon Regeneration Is Regulated by Ets-C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways

PLoS Genet. 2015 Oct 20;11(10):e1005603. doi: 10.1371/journal.pgen.1005603. eCollection 2015 Oct.


The ability of specific neurons to regenerate their axons after injury is governed by cell-intrinsic regeneration pathways. In Caenorhabditis elegans, the JNK and p38 MAPK pathways are important for axon regeneration. Axonal injury induces expression of the svh-2 gene encoding a receptor tyrosine kinase, stimulation of which by the SVH-1 growth factor leads to activation of the JNK pathway. Here, we identify ETS-4 and CEBP-1, related to mammalian Ets and C/EBP, respectively, as transcriptional activators of svh-2 expression following axon injury. ETS-4 and CEBP-1 function downstream of the cAMP and Ca2+-p38 MAPK pathways, respectively. We show that PKA-dependent phosphorylation of ETS-4 promotes its complex formation with CEBP-1. Furthermore, activation of both cAMP and Ca2+ signaling is required for activation of svh-2 expression. Thus, the cAMP/Ca2+ signaling pathways cooperatively activate the JNK pathway, which then promotes axon regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism*
  • Axons / physiology
  • CCAAT-Enhancer-Binding Proteins / biosynthesis
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development
  • Caenorhabditis elegans Proteins / biosynthesis
  • Caenorhabditis elegans Proteins / genetics*
  • Calcium Signaling / genetics
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism
  • Gene Expression Regulation, Developmental
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • MAP Kinase Signaling System / genetics
  • Neurons / metabolism
  • Phosphorylation
  • Regeneration / genetics*
  • Signal Transduction / genetics
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • p38 Mitogen-Activated Protein Kinases / genetics


  • CCAAT-Enhancer-Binding Proteins
  • Caenorhabditis elegans Proteins
  • ETS-4 protein, C elegans
  • Intercellular Signaling Peptides and Proteins
  • SVH-1 protein, C elegans
  • Transcription Factors
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases

Grant support

This research was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to NH and KM) (, as well as from the Naito Foundation ( and the Daiko Foundation (to NH) ( These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.