A Two-Immunoglobulin-Domain Transmembrane Protein Mediates an Epidermal-Neuronal Interaction to Maintain Synapse Density

•The IgSF protein ZIG-10 is required to maintain synapse density•ZIG-10 mediates an interaction between excitatory neurons and epidermis•ZIG-10 signals through Src kinase to regulate phagocytosis in epidermis•ZIG-10 activity modulates epileptic-like convulsions

SummarySynaptic maintenance is essential for neural circuit function. In the C. elegans locomotor circuit, motor neurons are in direct contact with the epidermis. Here, we reveal a novel epidermal-neuronal interaction mediated by a two-immunoglobulin domain transmembrane protein, ZIG-10, that is necessary for maintaining cholinergic synapse density. ZIG-10 is localized at the cell surface of epidermis and cholinergic motor neurons, with high levels at areas adjacent to synapses. Loss of zig-10 increases the number of cholinergic excitatory synapses and exacerbates convulsion behavior in a seizure model. Mis-expression of zig-10 in GABAergic inhibitory neurons reduces GABAergic synapse number, dependent on the presence of ZIG-10 in the epidermis. Furthermore, ZIG-10 interacts with the tyrosine kinase SRC-2 to regulate the phagocytic activity of the epidermis to restrict cholinergic synapse number. Our studies demonstrate the highly specific roles of non-neuronal cells in modulating neural circuit function, through neuron-type-specific maintenance of synapse density.