LRRTM2 Functions as a Neurexin Ligand in Promoting Excitatory Synapse Formation

• Published in: Neuron (Cambridge, Mass.) Vol. 64; no. 6; pp. 791 - 798
• Main Authors: Ko, Jaewon, Fuccillo, Marc V., Malenka, Robert C., Südhof, Thomas C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2009; Elsevier Limited
• Subjects: Alternative Splicing - genetics; Animals; Calcium-Binding Proteins; Cell Adhesion - genetics; Cell Adhesion Molecules, Neuronal; Cell Differentiation - physiology; Cell Line; CELLBIO; Cells, Cultured; Central Nervous System - embryology; Central Nervous System - metabolism; Chlorocebus aethiops; COS Cells; Excitatory Postsynaptic Potentials - genetics; Experiments; Humans; Ligands; Membrane Proteins - genetics; Membrane Proteins - metabolism; MOLNERO; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Cell Adhesion Molecules - genetics; Neural Cell Adhesion Molecules - metabolism; Neural Pathways - embryology; Neural Pathways - metabolism; Neurons; Peptides; Plasmids; Protein Binding - genetics; Proteins; Rats; Recombinant Proteins - pharmacology; RNA Splice Sites - genetics; Signal Transduction - physiology; SIGNALING; Synapses - genetics; Synapses - metabolism; Transfection; CELLBIO; MOLNERO; SIGNALING
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2009.12.012

Recently, leucine-rich repeat transmembrane proteins (LRRTMs) were found to be synaptic cell-adhesion molecules that, when expressed in nonneuronal cells, induce presynaptic differentiation in contacting axons. We now demonstrate that LRRTM2 induces only excitatory synapses, and that it also acts to induce synapses in transfected neurons similarly to neuroligin-1. Using affinity chromatography, we identified α- and β-neurexins as LRRTM2 ligands, again rendering LRRTM2 similar to neuroligin-1. However, whereas neuroligins bind neurexins containing or lacking an insert in splice site #4, LRRTM2 only binds neurexins lacking an insert in splice site #4. Binding of neurexins to LRRTM2 can produce cell-adhesion junctions, consistent with a trans-interaction regulated by neurexin alternative splicing, and recombinant neurexin-1β blocks LRRTM2’s ability to promote presynaptic differentiation. Thus, our data suggest that two unrelated postsynaptic cell-adhesion molecules, LRRTMs and neuroligins, unexpectedly bind to neurexins as the same presynaptic receptor, but that their binding is subject to distinct regulatory mechanisms.