biostudies-literatureSticco MJNCATS NIH HHSSwiss National Science FoundationNIDA NIH HHSCharles H. Hood FoundationNational Institutes of HealthNational Institute on Drug AbuseNIH HHSMax-Planck-Gesellschafte21194https://www.ebi.ac.uk/biostudies/studies/S-EPMC11565477biostudies-literatureUnknown35(1)Synapses are the fundamental structural unit by which neurons communicate. An orchestra of proteins regulates diverse synaptic functions, including synapse formation, maintenance, and elimination-synapse homeostasis. Some proteins of the larger C1q super-family are synaptic organizers involved in crucial neuronal processes in various brain regions. C1Q-like (C1QL) proteins bind to the adhesion G protein-coupled receptor B3 (ADGRB3) and act at synapses in a subset of circuits. To investigate the hypothesis that the secreted C1QL proteins mediate tripartite trans-synaptic adhesion complexes, we conducted an in vivo interactome study and identified new binding candidates. We demonstrate that C1QL3 mediates a novel cell-cell adhesion complex involving ADGRB3 and two neuronal pentraxins, NPTX1 and NPTXR. Analysis of single-cell RNA-Seq data from the cerebral cortex shows that C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons. Thus, our results suggest the possibility that in vivo the three co-expressed proteins are presynaptically secreted and form a complex capable of binding to postsynaptically localized ADGRB3, thereby creating a novel trans-synaptic adhesion complex. Identifying new binding partners for C1QL proteins and deciphering their underlying molecular principles will accelerate our understanding of their role in synapse organization.FASEB journal : official publication of the Federation of American Societies for Experimental BiologyC1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins.PMC11565477F32 DA031654166815CRETP3_166815#UL1TR001108UL1 TR001108Thompson BLFoldy CPena Palomino PALukacsovich DSticco MJMartinelli DCRessl SfalseC1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins.Synapses are the fundamental structural unit by which neurons communicate. An orchestra of proteins regulates diverse synaptic functions, including synapse formation, maintenance, and elimination-synapse homeostasis. Some proteins of the larger C1q super-family are synaptic organizers involved in crucial neuronal processes in various brain regions. C1Q-like (C1QL) proteins bind to the adhesion G protein-coupled receptor B3 (ADGRB3) and act at synapses in a subset of circuits. To investigate the hypothesis that the secreted C1QL proteins mediate tripartite trans-synaptic adhesion complexes, we conducted an in vivo interactome study and identified new binding candidates. We demonstrate that C1QL3 mediates a novel cell-cell adhesion complex involving ADGRB3 and two neuronal pentraxins, NPTX1 and NPTXR. Analysis of single-cell RNA-Seq data from the cerebral cortex shows that C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons. Thus, our results suggest the possibility that in vivo the three co-expressed proteins are presynaptically secreted and form a complex capable of binding to postsynaptically localized ADGRB3, thereby creating a novel trans-synaptic adhesion complex. Identifying new binding partners for C1QL proteins and deciphering their underlying molecular principles will accelerate our understanding of their role in synapse organization.2021-01-01T00:00:00Z2021 Jan2026-06-02T03:35:02.952Z2025-04-04T12:01:02.059ZS-EPMC115654773333755310.1096/fj.202000351RR10.1096/fj.202000351rr