Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Abstract

Neuroligins (NLGNs) organize neuronal connectivity by engaging a diverse set of interaction partners, yet how extracellular recognition couples to intracellular growth programs remains unclear. Using affinity proteomics, we identify intercellular adhesion molecule-5 (ICAM5), a cell-surface protein localized to dendritic filopodia, as a novel neuroligin interactor. Surface plasmon resonance and cell-based assays demonstrate direct binding between the ICAM5 and NLGN3 extracellular domains and reveal that ICAM5 engages all neuroligin isoforms. ICAM5 is required for NLGN-induced dendritic outgrowth, but the NLGN3-ICAM5 complex does not contribute to synaptogenesis. Mechanistically, ICAM5 sustains PAK-Cofilin signaling and F-actin organization in growth cones, positioning it as a downstream effector that links neuroligin engagement to actin remodeling. Together, these findings define a neuroligin-ICAM5 axis that couples extracellular recognition to intracellular actin remodeling to control neuronal structural development.