Cell-intrinsic regulation of presynaptic release site patterning

Abstract Functional neuronal connectivity depends not only on synaptic partner choice but also on the number, strength, and spatial distribution of release sites between partners. How these features are regulated remains poorly understood. Here, using the C. elegans DA9 motor neuron, we identify the immunoglobulin superfamily cell adhesion molecules SYG-1 and SYG-2 as cell-autonomous regulators of presynaptic release-site patterning. SYG-2 regulates presynapse number, size, and spacing, whereas SYG-1 primarily regulates spacing. Endogenous localization and cell-specific knockout analyses reveal that SYG-2 recruits SYG-1 to the presynaptic domain through previously unrecognized cis interactions. Endogenous structure-function studies further demonstrate that the SYG-2 intracellular domain is required for presynaptic organization and can promote presynapse formation independently of its extracellular domain. Genetic and targeted actin-disruption experiments implicate the adaptor protein NCK-1 and local actin remodeling in SYG-2 intracellular signaling. Together, these findings reveal how cell adhesion molecules can act cell-intrinsically to pattern presynaptic release sites after synaptic partners have been established.