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.
Authors
- Wim G. Annaert (ORCID: https://orcid.org/0000-0003-0150-9661)
- Luís F. Ribeiro (ORCID: https://orcid.org/0000-0003-1790-6848)
- Julie Nys
- Joris Vandenbempt (ORCID: https://orcid.org/0009-0004-9012-4775)
- Joris de Wit (ORCID: https://orcid.org/0000-0003-1120-1089)
- Jeffrey N. Savas (ORCID: https://orcid.org/0000-0002-8173-5580)
- Jonathan Elegheert (ORCID: https://orcid.org/0000-0002-4196-4813)
- Nuno Apóstolo (ORCID: https://orcid.org/0000-0001-6449-6306)
- Brigitt Raux (ORCID: https://orcid.org/0000-0002-2194-0259)
- Keimpe D. B. Wierda (ORCID: https://orcid.org/0000-0002-8784-9490)
- Eline Creemers (ORCID: https://orcid.org/0000-0002-9675-8195)
- Jeroen Vandensteen (ORCID: https://orcid.org/0009-0004-5084-7696)
- Beatriz Marques
- Cydric Geyskens (ORCID: https://orcid.org/0000-0002-1109-8221)
- Ellis Boonen
- llkem Kumru
- João F. Machado
Institutions
- Northwestern University (US)
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Institut Interdisciplinaire de Neuroscience (FR)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Centro de Inovação em Biomedicina e Biotecnologia (PT)
- Multidisciplinary Institute of Ageing (PT)
- University of Coimbra (PT)
- KU Leuven (BE)
Publication Details
- Journal
- iScience
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1016/j.isci.2026.117906
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fonds Wetenschappelijk Onderzoek
- Conseil Régional Aquitaine
- Fundação para a Ciência e a Tecnologia
- H2020 Marie Skłodowska-Curie Actions