title: Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing.
abstract: Latrophilin-1, -2, and -3 are adhesion-type G protein-coupled receptors that are auxiliary α-latrotoxin receptors, suggesting that they may have a synaptic function. Using pulldowns, we here identify teneurins, type II transmembrane proteins that are also candidate synaptic cell-adhesion molecules, as interactors for the lectin-like domain of latrophilins. We show that teneurin binds to latrophilins with nanomolar affinity and that this binding mediates cell adhesion, consistent with a role of teneurin binding to latrophilins in trans-synaptic interactions. All latrophilins are subject to alternative splicing at an N-terminal site; in latrophilin-1, this alternative splicing modulates teneurin binding but has no effect on binding of latrophilin-1 to another ligand, FLRT3. Addition to cultured neurons of soluble teneurin-binding fragments of latrophilin-1 decreased synapse density, suggesting that latrophilin binding to teneurin may directly or indirectly influence synapse formation and/or maintenance. These observations are potentially intriguing in view of the proposed role for Drosophila teneurins in determining synapse specificity. However, teneurins in Drosophila were suggested to act as homophilic cell-adhesion molecules, whereas our findings suggest a heterophilic interaction mechanism. Thus, we tested whether mammalian teneurins also are homophilic cell-adhesion molecules, in addition to binding to latrophilins as heterophilic cell-adhesion molecules. Strikingly, we find that although teneurins bind to each other in solution, homophilic teneurin-teneurin binding is unable to support stable cell adhesion, different from heterophilic teneurin-latrophilin binding. Thus, mammalian teneurins act as heterophilic cell-adhesion molecules that may be involved in trans-neuronal interaction processes such as synapse formation or maintenance.
authors.affiliation: From the Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94305.
authors.forename: Antony A
authors.initials: AA
authors.lastname: Boucard
authors.forename: Stephan
authors.initials: S
authors.lastname: Maxeiner
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D018000:Receptors, Peptide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019063:Tenascin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D018000:Receptors, Peptide; D019063:Tenascin; C034800:alpha-latrotoxin receptor
keywords: Alternative Splicing; Cell Adhesion; FLRT3; G Protein-coupled Receptors (GPCR); Ligand-binding Protein; Neurexin; Neurons; Synapse Formation; Teneurin; α-Latrotoxin