A Receptor Tyrosine Kinase Network Regulates Neuromuscular Function in Response to Oxidative Stress in Caenorhabditis elegans

The transcription factor Nrf2 plays a critical role in the organism-wide regulation of the antioxidant stress response. The Nrf2 homolog functions in the intestinal cells nonautonomously to negatively regulate neuromuscular junction (NMJ) function in Caenorhabditis elegans. To identify additional molecules that mediate signaling to the NMJ, we performed a candidate screen for suppressors of aldicarb resistance caused by acute treatment with the activator arsenite. We identified two receptor tyrosine kinases, (fibroblast growth factor receptor, FGFR) and (insulin-like peptide receptor), that are required for NMJ regulation in response to stress. Through double-mutant analysis, we found that functions downstream of, or parallel to, and (sphingosine kinase), and that the ligand FGF and canonical effectors are required for oxidative stress-mediated regulation of NMJ function. also functions downstream of or parallel to 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 occurs via a complex organism-wide signaling network involving receptor tyrosine kinase signaling in multiple tissues.