Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing*
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Cell Adhesion / physiology
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Cell Adhesion Molecules, Neuronal
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Cells, Cultured
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Chromatography, Affinity / methods
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Electrophoretic Mobility Shift Assay / methods
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Glycoproteins / classification
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Glycoproteins / metabolism*
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Green Fluorescent Proteins / metabolism
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Hippocampus / cytology*
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Humans
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Immunohistochemistry / methods
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Microtubule-Associated Proteins / metabolism
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Mutagenesis / physiology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / metabolism*
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Neuropeptides / classification
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Neuropeptides / metabolism*
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Protein Binding / physiology
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Rats
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Recombinant Proteins / biosynthesis
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Synapses / metabolism*
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Synapsins / metabolism
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Transfection / methods
Substances
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Cell Adhesion Molecules, Neuronal
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Glycoproteins
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MAP2 protein, rat
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Membrane Proteins
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Neuropeptides
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Recombinant Proteins
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Synapsins
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enhanced green fluorescent protein
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neurexophilin
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neuroligin 1
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Green Fluorescent Proteins