L1CAMs are immunoglobulin cell adhesion molecules that are linked to diverse neurological conditions, including intellectual disability, autism, and schizophrenia. Studies in C. elegans and mice revealed L1CAM developmental roles that include axon guidance and dendrite morphogenesis, as well as maintenance of neural integrity. We recently uncovered a non-developmental role for the C. elegans L1CAM encoded by the
sax-7 gene in promoting coordinated locomotion.
sax-7 genetically interacts with
rab-3,
unc-13, and
snb-1, genes that function in the synaptic vesicle cycle, resulting in synthetic or synergistic uncoordinated (Unc) locomotion. To determine the basis of the synthetic Unc, we performed a genetic suppressor screen and identified loss-of-function mutations in
ksr-1, which encodes for a scaffold that facilitates MPK-1/Erk activation. Indeed, we provide data showing that loss of MPK-1 also suppresses
rab-3;
sax-7 synthetic Unc locomotion. Further analyses reveal that loss of
ksr-1 suppresses the abnormal response
rab-3;
sax-7 animals display to an acetylcholinesterase inhibitor, consistent with defects in the synaptic vesicle cycle.In addition to these genetic and behavioral data, we conducted electrophysiological and high-pressure electron microscopy analyses to examine how SAX-7 and MPK-1/Erk signaling promote coordinated locomotion. These functional data provide new insights into the interpretation of the behavioral phenotypes and the underlying circuitry involved.