Abstract
The clustering of neurotransmitter receptors at appropriate postsynaptic sites is essential for controlling synaptic transmission. While most known mechanisms involve receptor binding with cytoplasmic scaffolds, recent evidence highlights the importance of extracellular interactions that directly target receptors. Using Caenorhabditis elegans, we identified a trans-synaptic complex that involves RIG-5 and ZIG-8, two adhesion molecules of the immunoglobulin (Ig) superfamily and orthologous to Drosophila DIPs and Dprs, and mammalian IgLONs. Our results show that RIG-5 and ZIG-8 are anchored in the pre- and postsynaptic membranes, respectively, and interact in vivo via their first Ig domains. Furthermore, ZIG-8 directly binds a α7-like acetylcholine receptor (AChR), known as ACR-16, via a cis-interaction between its Ig2 domain and the base of the extracellular AChR domain. This study provides direct evidence that trans-synaptic IgLON interactions can organize neurochemical synapses and suggests that the IgLONs may directly interact with ionotropic receptors in the mammalian nervous system.
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Data availability
Source data are provided with this paper. The plasmids and C. elegans strains generated in this study are available from the corresponding authors upon request. Source data are provided with this paper.
Code availability
The code used to perform analyses of synapse density is deposited on Zenodo, and is accessible via (https://doi.org/10.5281/zenodo.17571550)95.
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Acknowledgements
We thank members of the Bessereau lab for providing feedback, Mélissa Cizeron for advice on image analysis, Driss Laabid and Lina Boumasmoud for technical assistance, and Océane Romatif, Delphine Le Guern and Camille Vachon for strains. We are grateful to Elise Forgues, Cecile Chatras, Mathieu Ben Abu and Manon Courtieux for their help during their respective internships. We thank Pierre-Jean Corringer for critical reading of the manuscript, Mei Zhen and Jun Meng for providing information on neuronal promoters, Alexander Gottschalk for sharing plasmids and Eviatar Yemini for advice on NeuroPAL. We thank the Caenorhabditis Genetics Center (CGC), funded by NIH Office of Research Infrastructure Programs (P40 OD010440), for providing strains. We thank the SFR Biosciences (University Lyon 1 CNRS UAR 3444 INSERM US8, ENS de Lyon), Matthieu Caron and Francesca Palladino for access to equipment. We thank Le Centre d’Imagerie Quantitative Lyon-Est (LyMIC-CIQLE, Lyon, France) imaging facility for support and access to equipment, and Camilla Luccardini for technical assistance. Some strains were generated by SEGiCel (SFR Santé Lyon Est CNRS UAR 3453, Lyon, France) with the support of CNRS and IBiSA. Some graphical elements in Figs. 1d and 6b were provided by Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This work was supported as follows: M.M.: fellowship from the French Ministry of Research; BPL: LABEX Cortex (ANR-11-LABX-0042) of University Lyon 1, within the program “Investissements d’Avenir” (ANR-11-IDEX-0007) and Fondation pour la Recherche Médicale grant (FRM-MND-202411019867); EÖ: National Institutes of Health, National Institute of Neurological Disorders and Stroke grant R01 NS139060 grant; JLB: Équipe FRM 2023 EQU202303016267, ANR Synapunct ANR-22CE16-0024-01, ERC_Adg C.NAPSE #695295, ANR-11-LABX-0042/ANR-11-IDEX-0007.
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Conceptualization: M.M., J.-L.B. and B.P.-L.; Methodology: M.M., A.W., E.Ö., J.-L.B. and B.P.-L.; Investigation: M.M., L.P., L. G. and B.P.-L.; Formal analysis: M.M., L.P., E.Ö. and B.P.-L.; Visualization: M.M., E.Ö., J.-L.B. and B.P.-L.; Writing – Original Draft: M.M., J.-L.B. and B.P.-L.; Writing – Review & Editing: M.M., A.W., E.Ö., J.-L.B. and B.P.-L.; Funding Acquisition: E.Ö., J.-L.B. and B.P.-L.; Supervision: J.-L.B. and B.P.-L.
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Mialon, M., Patrash, L., Granger, L. et al. A trans-synaptic IgLON adhesion molecular complex directly contacts and clusters a nicotinic receptor. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68141-1
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DOI: https://doi.org/10.1038/s41467-025-68141-1
