Structurally, LPHNs are characterized by a seven-transmembrane region and a large N-terminal extracellular sequence containing the following domains: a rhamnose binding lectin (RBL) domain; an olfactomedin-like (OLF) domain followed by a Serine/Threonine rich domain that is O-linked glycosylated (O’Sullivan et al., 2014); a hormone binding (HR) domain; a GPCR Autoproteolysis INducing (GAIN) domain (Figure 1A). We recently reported that LPHN3 binds in vivo and in vitro to fibronectin leucine-rich repeat transmembrane 3 (FLRT3) to constitute a synaptic ligand-receptor pair that can modulate excitatory synapse number (O’Sullivan et al., 2012). There are three FLRT genes, FLRT1-3, encoding single-pass transmembrane proteins with one extracellular leucine-rich repeat (LRR) domain and a juxtamembrane fibronectin type 3 (FNIII) module (Lacy et al., 1999). Synaptic puncta density and cell based binding experiments using deletion of the OLF or the OLF-RBL domains prevented rescue of the synaptic phenotype, and suggested that whereas the OLF domain is required for interaction with FLRTs, both the RBL and OLF domains are involved in the interaction with teneurin 1 (TEN1), a cell surface protein involved in brain development. These data indicate
