Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Cydric Geyskens; Brigitt Raux; Nuno Apóstolo; Ellis Boonen; Jeroen Vandensteen; Beatriz Marques; João Machado; llkem Kumru; Julie Nys; Eline Creemers; Joris Vandenbempt; Keimpe D. B. Wierda; Wim G. Annaert; Jeffrey N. Savas; Joris de Wit; Jonathan Elegheert; Luís F. Ribeiro

doi:10.1016/j.isci.2026.117906

NeuroscienceiScienceOct 29, 2026

Peer-reviewed journal article

Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Cydric Geyskens iD, Brigitt Raux iD, Nuno Apóstolo iD, Ellis Boonen, Jeroen Vandensteen iD, Beatriz Marques, João Machado, llkem Kumru, Julie Nys, Eline Creemers iD, Joris Vandenbempt iD, Keimpe D. B. Wierda iD, Wim G. Annaert iD, Jeffrey N. Savas iD, Joris de Wit iD, Jonathan Elegheert iD, Luís F. Ribeiro iD

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.

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