The L1CAM SAX-7 is an antagonistic modulator of Erk Signaling

Abstract L1CAMs are immunoglobulin superfamily cell adhesion molecules that ensure proper nervous system development and function. In addition to being associated with the autism and schizophrenia spectrum disorders, mutations in the L1CAM family of genes also underlie distinct developmental syndromes with neurological conditions, such as intellectual disability, spastic paraplegia, hypotonia and congenital hydrocephalus. Studies in both vertebrate and invertebrate model organisms have established conserved neurodevelopmental roles for L1CAMs; these include axon guidance, dendrite morphogenesis, synaptogenesis, and maintenance of neural architecture, among others. In Caenorhabditis elegans , L1CAMs, encoded by the sax-7 gene, are required for coordinated locomotion. We previously uncovered a genetic interaction between sax-7 and components of synaptic vesicle cycle, revealing a non-developmental role for sax-7 in regulating synaptic activity. More recently, we determined that sax-7 also genetically interacts with extracellular signal-related kinase (ERK) signaling in controlling coordinated locomotion. C. elegans ERK, encoded by the mpk-1 gene, is a serine/threonine protein kinase belonging to the mitogen-activated protein kinase (MAPK) family that governs multiple aspects of animal development and cellular homeostasis. Here, we show this genetic interaction between sax-7 and mpk-1 occurs not only in cholinergic neurons for coordinated locomotion, but also extends outside the nervous system, revealing novel roles for SAX-7/L1CAM in non-neuronal processes, including vulval development. Our genetic findings in both the nervous system and developing vulva are consistent with SAX-7/L1CAM acting as an antagonistic modulator of ERK signaling.