Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Geyskens, C.; Raux, B.; Apostolo, N.; Boonen, E.; Vandensteen, J.; Marques, B.; Machado, J. F.; Kumru, l.; Nys, J.; Creemers, E.; Vandenbempt, J.; Wierda, K.; Annaert, W.; Savas, J. N.; de Wit, J.; Elegheert, J.; Ribeiro, L. F.

doi:10.64898/2026.03.06.709873

bioRxiv · 10.64898/2026.03.06.709873

Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling

Geyskens, C.·Raux, B.·Apostolo, N.·Boonen, E.·Vandensteen, J.·Marques, B.·Machado, J. F.·Kumru, l.·Nys, J.·Creemers, E.·Vandenbempt, J.·Wierda, K.·Annaert, W.·Savas, J. N.·de Wit, J.·Elegheert, J.·Ribeiro, L. F.

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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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Geyskens, C., Raux, B., Apostolo, N., Boonen, E., Vandensteen, J., Marques, B., Machado, J. F., Kumru, l., Nys, J., Creemers, E., Vandenbempt, J., Wierda, K., Annaert, W., Savas, J. N., de Wit, J., Elegheert, J., Ribeiro, L. F.. 2026-03-06. Extracellular neuroligin-ICAM5 coupling drives dendritic growth via actin remodeling. https://doi.org/10.64898/2026.03.06.709873

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