RRC ID 59520
Author Kim S, Sieburth D.
Title A Receptor Tyrosine Kinase Network Regulates Neuromuscular Function in Response to Oxidative Stress in Caenorhabditis elegans.
Journal Genetics
Abstract The transcription factor Nrf2 plays a critical role in the organism-wide regulation of the antioxidant stress response. The Nrf2 homolog SKN-1 functions in the intestinal cells nonautonomously to negatively regulate neuromuscular junction (NMJ) function in Caenorhabditis elegans To identify additional molecules that mediate SKN-1 signaling to the NMJ, we performed a candidate screen for suppressors of aldicarb resistance caused by acute treatment with the SKN-1 activator arsenite. We identified two receptor tyrosine kinases, EGL-15 (fibroblast growth factor receptor, FGFR) and DAF-2 (insulin-like peptide receptor), that are required for NMJ regulation in response to stress. Through double-mutant analysis, we found that EGL-15 functions downstream of, or parallel to, SKN-1 and SPHK-1 (sphingosine kinase), and that the EGL-15 ligand EGL-17 FGF and canonical EGL-15 effectors are required for oxidative stress-mediated regulation of NMJ function. DAF-2 also functions downstream of or parallel to SKN-1 to regulate NMJ function. Through tissue-specific rescue experiments, we found that FGFR signaling functions primarily in the hypodermis, whereas insulin-like peptide receptor signaling is required in multiple tissues. Our results support the idea that the regulation of NMJ function by SKN-1 occurs via a complex organism-wide signaling network involving receptor tyrosine kinase signaling in multiple tissues.
Volume 211(4)
Pages 1283-1295
Published 2019-4-1
DOI 10.1534/genetics.119.302026
PII genetics.119.302026
PMID 30782598
PMC PMC6456306
MeSH Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism Neuromuscular Junction / metabolism* Neuromuscular Junction / physiology Oxidative Stress* Phosphotransferases (Alcohol Group Acceptor) / genetics Phosphotransferases (Alcohol Group Acceptor) / metabolism Receptor, Insulin / genetics Receptor, Insulin / metabolism* Receptors, Fibroblast Growth Factor / genetics Receptors, Fibroblast Growth Factor / metabolism* Signal Transduction* Transcription Factors / genetics Transcription Factors / metabolism
IF 3.564
Times Cited 0
C.elegans tm1711 tm1053 tm1353 tm1108 tm6496 tm5634 tm1589 tm1718