A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning

Crawley, Oliver; Giles, Andrew C.; Desbois, Muriel; Kashyap, Sudhanva; Birnbaum, Rayna; Grill, Brock

Abstract

The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new MAP kinase pathway that suppresses synapse formation defects, but not axon termination defects, in the mechanosensory neurons of rpm-1 mutants. This pathway includes: MIG-15 (MAP4K), NSY-1 (MAP3K), JKK-1 (MAP2K) and JNK-1 (MAPK). Transgenic overexpression of kinases in the MIG-15/JNK-1 pathway is sufficient to impair synapse formation in wild-type animals. The MIG-15/JNK-1 pathway functions cell autonomously in the mechanosensory neurons, and these kinases localize to presynaptic terminals providing further evidence of a role in synapse development. Loss of MIG-15/JNK-1 signaling also suppresses defects in habituation to repeated mechanical stimuli in rpm-1 mutants, a behavioral deficit that is likely to arise from impaired glutamatergic synapse formation. Interestingly, habituation results are consistent with the MIG-15/JNK-1 pathway functioning as a parallel opposing pathway to RPM-1. These findings indicate the MIG-15/JNK-1 pathway can restrict both glutamatergic synapse formation and short-term learning.

Citation

Crawley, O., Giles, A. C., Desbois, M., Kashyap, S., Birnbaum, R., & Grill, B. (2017). A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. PLOS genetics, 13(12), Article e1007095. https://doi.org/10.1371/journal.pgen.1007095

• Journal Article Type: Article
• Acceptance Date: Nov 1, 2017
• Publication Date: Dec 11, 2017
• Deposit Date: Mar 1, 2024
• Journal: PLOS Genetics
• Print ISSN: 1553-7404
• Publisher: Public Library of Science (PLoS)
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 12
• Article Number: e1007095
• DOI: https://doi.org/10.1371/journal.pgen.1007095
• Publisher URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007095