Open AccessAxon Regeneration Is Regulated by Ets–C/EBP Transcription Complexes Generated by Activation of the cAMP/Ca2+ Signaling Pathways
Author(s) -
Chun Li,
Naoki Hisamoto,
Kunihiro Matsumoto
Publication year - 2015
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1005603
Subject(s) - biology , microbiology and biotechnology , signal transduction , axon , regeneration (biology) , transcription factor , mapk/erk pathway , phosphorylation , p38 mitogen activated protein kinases , caenorhabditis elegans , kinase , ccaat enhancer binding proteins , gene , genetics , dna binding protein
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 Ca 2+ –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 Ca 2+ signaling is required for activation of svh-2 expression. Thus, the cAMP/Ca 2+ signaling pathways cooperatively activate the JNK pathway, which then promotes axon regeneration.