A role for the Erk MAPK pathway in modulating SAX-7/L1CAM-dependent locomotion in Caenorhabditis elegans

Abstract

L1CAMs are immunoglobulin cell adhesion molecules that play important roles in the development and function of the nervous system. In addition to being associated with autism and schizophrenia spectrum disorders, impaired L1CAM function also underlies the X-linked L1 syndrome, which encompasses a group of neurological conditions, including spastic paraplegia and congenital hydrocephalus. Previous studies on both vertebrate and invertebrate L1CAMs established conserved roles that include axon guidance, dendrite morphogenesis, synapse development, and maintenance of neural architecture. We previously identified a genetic interaction between the C. elegans L1CAM encoded by the sax-7 gene and RAB-3, a GTPase that functions in synaptic neurotransmission; rab-3; sax-7 animals exhibit synthetic locomotion abnormalities and neuronal dysfunction. In this study, we examine the significance of this genetic interaction and show that this synergism also occurs when loss of SAX-7 is combined with mutants of other genes encoding key players of the synaptic vesicle cycle. In contrast, sax-7 does not interact with genes that function in synaptogenesis. These findings suggest a post-developmental role for sax-7 in the regulation of synaptic activity. To further assess this possibility, we conducted electrophysiological recordings and ultrastructural analyses at neuromuscular junctions. Lastly, we performed a forward genetic screen for suppressors of the rab-3; sax-7 synthetic phenotypes, uncovering a role for the Mitogen-activated Protein Kinase (MAPK) pathway in promoting coordinated locomotion.