Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

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 NLGN interactor. Surface plasmon resonance and cell-based assays demonstrate direct binding between the ICAM5 and NLGN3 extracellular domains and reveal that ICAM5 engages all NLGN isoforms. In neurons, NLGN3 and ICAM5 preferentially colocalize at extrasynaptic, F-actin-positive dendritic sites, linking this interaction to regions of active cytoskeletal reorganization and growth. Accordingly, ICAM5 strongly enhances NLGN-induced dendritic outgrowth, but the NLGN3-ICAM5 complex does not detectably contribute to synaptogenesis. Mechanistically, ICAM5 sustains PAK-cofilin signaling and F-actin organization in growth cones, positioning it as a modulator linking NLGN engagement to actin remodeling. Together, these findings define a NLGN-ICAM5 axis that couples extracellular recognition to intracellular cytoskeletal remodeling to control neuronal structural development.