A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins.
Previous studies suggested that postsynaptic neuroligins form a trans-synaptic complex with presynaptic beta-neurexins, but not with presynaptic alpha-neurexins. Unexpectedly, we now find that neuroligins also bind alpha-neurexins and that alpha- and beta-neurexin binding by neuroligin 1 is regulated by alternative splicing of neuroligin 1 (at splice site B) and of neurexins (at splice site 4). In neuroligin 1, splice site B is a master switch that determines alpha-neurexin binding but leaves beta-neurexin binding largely unaffected, whereas alternative splicing of neurexins modulates neuroligin binding. Moreover, neuroligin 1 splice variants with distinct neurexin binding properties differentially regulate synaptogenesis: neuroligin 1 that binds only beta-neurexins potently stimulates synapse formation, whereas neuroligin 1 that binds to both alpha- and beta-neurexins more effectively promotes synapse expansion. These findings suggest that neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation, indicating that expression of different neuroligin and neurexin isoforms specifies a trans-synaptic signaling code.
Boucard
Antony A
AA
Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard NA4.118, Dallas, Texas 75390, USA.
Chubykin
Alexander A
AA
Comoletti
Davide
D
Taylor
Palmer
P
Südhof
Thomas C
TC
D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002448:Cell Adhesion / Q000502:physiology; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D002846:Chromatography, Affinity / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D006023:Glycoproteins / Q000145:classification / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000145:classification / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis; D013569:Synapses / Q000378:metabolism*; D016704:Synapsins / Q000378:metabolism; D014162:Transfection / Q000379:methods
D015816:Cell Adhesion Molecules, Neuronal; D006023:Glycoproteins; C489787:MAP2 protein, rat; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D011994:Recombinant Proteins; D016704:Synapsins; C485184:enhanced green fluorescent protein; C112162:neurexophilin; C093438:neuroligin 1; D049452:Green Fluorescent Proteins