LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation.
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 alpha- and beta-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-1beta 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.
Ko
Jaewon
J
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
Fuccillo
Marc V
MV
Malenka
Robert C
RC
Südhof
Thomas C
TC
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology* / Q000378:metabolism*; D002522:Chlorocebus aethiops; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009434:Neural Pathways / Q000196:embryology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008024:Ligands; D008565:Membrane Proteins; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D022821:RNA Splice Sites; D011994:Recombinant Proteins; C093438:neuroligin 1