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

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. © 2017 crawley et al.