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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Axons / metabolism*
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Axons / physiology
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CCAAT-Enhancer-Binding Proteins / biosynthesis
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CCAAT-Enhancer-Binding Proteins / genetics*
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / growth & development
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Caenorhabditis elegans Proteins / biosynthesis
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Caenorhabditis elegans Proteins / genetics*
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Calcium Signaling / genetics
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Cyclic AMP / genetics
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Cyclic AMP / metabolism
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Gene Expression Regulation, Developmental
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Intercellular Signaling Peptides and Proteins / genetics
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MAP Kinase Signaling System / genetics
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Neurons / metabolism
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Phosphorylation
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Regeneration / genetics*
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Signal Transduction / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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p38 Mitogen-Activated Protein Kinases / genetics
Substances
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CCAAT-Enhancer-Binding Proteins
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Caenorhabditis elegans Proteins
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ETS-4 protein, C elegans
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Intercellular Signaling Peptides and Proteins
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SVH-1 protein, C elegans
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Transcription Factors
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Cyclic AMP
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p38 Mitogen-Activated Protein Kinases