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.

Abstract

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

Substances

  • 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) (http://www.mext.go.jp/english/), as well as from the Naito Foundation (https://www.naito-f.or.jp/en/) and the Daiko Foundation (to NH) (http://www1.s3.starcat.ne.jp/daiko-f/). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.