A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins
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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.
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Many known ASD genes, such as neuroligins and neurexins, display complex isoform-specific expression in brain, with different isoforms having distinct functions.
“Consistent with this notion, many known ASD genes, such as neuroligins and neurexins, display a complex pattern of isoform-specific expression in brain (Boucard et al., 2005; Sudhof, 2008), with different isoforms having very distinct functions (Chih et al., 2006).”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Boucard et al., 2005
Cites
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Study, P. A. R. I. S., Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., et al. (2003) · Nature Genetics · doi:10.1038/ng1136 · Cited by 1,851 · see citing works
Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons
Scheiffele, P., Fan, J., Choih, J., Fetter, R., & Serafini, T. (2000) · Cell · doi:10.1016/s0092-8674(00)80877-6 · Cited by 1,060 · see citing works
Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins
Graf, E. R., Zhang, X., Jin, S., Linhoff, M. W., & Craig, A. M. (2004) · Cell · doi:10.1016/j.cell.2004.11.035 · Cited by 989 · see citing works
SynCAM, a Synaptic Adhesion Molecule That Drives Synapse Assembly
Biederer, T., Sara, Y., Mozhayeva, M. G., Atasoy, D., Liu, X., Kavalali, E. T., & Südhof, T. C. (2002) · Science · doi:10.1126/science.1072356 · Cited by 800 · see citing works
Self-citationControl of Excitatory and Inhibitory Synapse Formation by Neuroligins
Chih, B., Engelman, H. S., & Scheiffele, P. (2005) · Science · doi:10.1126/science.1107470 · Cited by 707 · see citing works
α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis
Missler, M., Zhang, W., Rohlmann, A., Kattenstroth, G., Hammer, R. E., Gottmann, K., & Südhof, T. C. (2003) · Nature · doi:10.1038/nature01755 · Cited by 699 · see citing works
Self-citationNeuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses
Song, J.-Y., Ichtchenko, K., Südhof, T. C., & Brose, N. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.3.1100 · Cited by 696 · see citing works
Self-citationNeurexins: Synaptic Cell Surface Proteins Related to the α-Latrotoxin Receptor and Laminin
Ushkaryov, Y. A., Petrenko, A. G., Geppert, M., & Südhof, T. C. (1992) · Science · doi:10.1126/science.1621094 · Cited by 682 · see citing works
Self-citationNeuroligin 1: A splice site-specific ligand for β-neurexins
Ichtchenko, K., Hata, Y., Nguyen, T., Ullrich, B., Missler, M., Moomaw, C. R., & Südhof, T. C. (1995) · Cell · doi:10.1016/0092-8674(95)90396-8 · Cited by 663 · see citing works
Self-citationNeurexin mediates the assembly of presynaptic terminals
Dean, C., Scholl, F. G., Choih, J., DeMaria, S., Berger, J., Isacoff, E., & Scheiffele, P. (2003) · Nature Neuroscience · doi:10.1038/nn1074 · Cited by 617 · see citing works
Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy
Moore, S. A., Saito, F., Chen, J., Michele, D. E., Henry, M. D., Messing, A., Cohn, R. D., Ross, S. E., Westra, S., Williamson, R. A., et al. (2002) · Nature · doi:10.1038/nature00838 · Cited by 574 · see citing works
Neuroligin 2 is exclusively localized to inhibitory synapses
Varoqueaux, F., Jamain, S., & Brose, N. (2004) · European Journal of Cell Biology · doi:10.1078/0171-9335-00410 · Cited by 552 · see citing works
Ullrich, B., Ushkaryov, Y. A., & Südhof, T. C. (1995) · Neuron · doi:10.1016/0896-6273(95)90306-2 · Cited by 460 · see citing works
Self-citationStructures, Alternative Splicing, and Neurexin Binding of Multiple Neuroligins
Ichtchenko, K., Nguyen, T., & Südhof, T. C. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.5.2676 · Cited by 459 · see citing works
Self-citationA stoichiometric complex of neurexins and dystroglycan in brain
Sugita, S., Saito, F., Tang, J., Satz, J., Campbell, K., & Südhof, T. (2001) · Journal of Cell Biology · doi:10.1083/jcb.200105003 · Cited by 453 · see citing works
Self-citationYamagata, M., Sanes, J. R., & Weiner, J. A. (2003) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(03)00107-8 · Cited by 374 · see citing works
A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin
Prange, O., Wong, T. P., Gerrow, K., Wang, Y. T., & El-Husseini, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405939101 · Cited by 363 · see citing works
Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients
Yan, J., Oliveira, G., Coutinho, A. P., Yang, C., Feng, J., Katz, C., Sram, J. P., Bockholt, A., Jones, I. R., Craddock, N. J., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001629 · Cited by 323 · see citing works
Structure and Evolution of Neurexin Genes: Insight into the Mechanism of Alternative Splicing
Tabuchi, K., & Südhof, T. C. (2002) · Genomics · doi:10.1006/geno.2002.6780 · Cited by 305 · see citing works
Self-citationNguyen, T., & Südhof, T. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.41.26032 · Cited by 234 · see citing works
Self-citationAnalysis of the Human Neurexin Genes: Alternative Splicing and the Generation of Protein Diversity
Rowen, L., Young, J. M., Birditt, B., Kaur, A., Madan, A., Philipps, D. L., Qin, S., Minx, P. J., Wilson, R. K., Hood, L., et al. (2002) · Genomics · doi:10.1006/geno.2002.6734 · Cited by 184 · see citing works
Missler, M., Fernández-Chacón, R., & Südhof, T. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71041339.x · Cited by 161 · see citing works
Self-citationUshkaryov, Y. A., Hata, Y., Ichtchenko, K., Moomaw, C. R., Afendis, S. J., Slaughter, C. A., & Südhof, T. C. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32671-6 · Cited by 160 · see citing works
Self-citationZhang, W., Rohlmann, A., Sargsyan, V., Aramuni, G., Hammer, R. E., Südhof, T. C., & Missler, M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.0497-05.2005 · Cited by 156 · see citing works
Self-citationActivity-dependent regulation of synaptic clustering in a hippocampal culture system
Kavalali, E. T., Klingauf, J., & Tsien, R. W. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12893 · Cited by 128 · see citing works
Characterization of the Interaction of a Recombinant Soluble Neuroligin-1 with Neurexin-1β
Comoletti, D., Flynn, R. E., Jennings, L. L., Chubykin, A. A., Matsumura, T., Hasegawa, H., Südhof, T. C., & Taylor, P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306803200 · Cited by 124 · see citing works
Self-citationNeurexophilin Binding to α-Neurexins
Missler, M., Hammer, R. E., & Südhof, T. C. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.52.34716 · Cited by 112 · see citing works
Self-citationFunctional Excitatory Synapses in HEK293 Cells Expressing Neuroligin and Glutamate Receptors
Fu, Z., Washbourne, P., Ortinski, P. I., & Vicini, S. (2003) · Journal of Neurophysiology · doi:10.1152/jn.00647.2003 · Cited by 110 · see citing works
Postsynaptic N -methyl- d -aspartate receptor function requires α-neurexins
Kattenstroth, G., Tantalaki, E., Südhof, T. C., Gottmann, K., & Missler, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308626100 · Cited by 108 · see citing works
Self-citationHoffman, R. C., Jennings, L. L., Tsigelny, I. F., Comoletti, D., Flynn, R. E., Südhof, T. C., & Taylor, P. (2004) · Biochemistry · doi:10.1021/bi035278t · Cited by 45 · see citing works
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Neuroligins and neurexins link synaptic function to cognitive disease
Südhof, T. C. (2008) · Nature · doi:10.1038/nature07456 · Cited by 1,849 · see citing works
Self-citationAdvances in autism genetics: on the threshold of a new neurobiology
Abrahams, B. S., & Geschwind, D. H. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2346 · Cited by 1,866 · see citing works
A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice
Tabuchi, K., Blundell, J., Etherton, M. R., Hammer, R. E., Liu, X., Powell, C. M., & Südhof, T. C. (2007) · Science · doi:10.1126/science.1146221 · Cited by 997 · see citing works
Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits
Südhof, T. C. (2017) · Cell · doi:10.1016/j.cell.2017.10.024 · Cited by 810 · see citing works
Self-citationChubykin, A. A., Atasoy, D., Etherton, M. R., Brose, N., Kavalali, E. T., Gibson, J. R., & Südhof, T. C. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.029 · Cited by 594 · see citing works
Self-citationDisruption of neurexin 1 associated with autism spectrum disorder
Kim, H.-G., Kishikawa, S., Higgins, A. W., Seong, I.-S., Donovan, D. J., Shen, Y., Lally, E., Weiss, L. A., Najm, J., Kutsche, K., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.09.011 · Cited by 578 · see citing works
Gao, R., & Penzes, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150303003028 · Cited by 516 · see citing works
“Despite these challenges, culture studies have shown that particular splice variants influence the formation of specific synapses [158, 177-180].”
BackgroundNanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses
Eggermann, E., Bucurenciu, I., Goswami, S. P., & Jonas, P. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3125 · Cited by 500 · see citing works
Uemura, T., Lee, S.-J., Yasumura, M., Takeuchi, T., Yoshida, T., Ra, M., Taguchi, R., Sakimura, K., & Mishina, M. (2010) · Cell · doi:10.1016/j.cell.2010.04.035 · Cited by 496 · see citing works
Modeling Autism by SHANK Gene Mutations in Mice
Jiang, Y.-H., & Ehlers, M. D. (2013) · Neuron · doi:10.1016/j.neuron.2013.03.016 · Cited by 488 · see citing works
Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior
Blundell, J., Blaiss, C. A., Etherton, M. R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M. F., Südhof, T. C., & Powell, C. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4517-09.2010 · Cited by 450 · see citing works
Self-citationChih, B., Gollan, L., & Scheiffele, P. (2006) · Neuron · doi:10.1016/j.neuron.2006.06.005 · Cited by 393 · see citing works
Neuronal regulation of alternative pre-mRNA splicing
Li, Q., Lee, J.-A., & Black, D. L. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2237 · Cited by 376 · see citing works
Xu, J., Mashimo, T., & Südhof, T. C. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.004 · Cited by 336 · see citing works
Self-citationCartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing
Treutlein, B., Gokce, O., Quake, S. R., & Südhof, T. C. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403244111 · Cited by 348 · see citing works
Self-citationTruncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia
Gauthier, J., Siddiqui, T. J., Huashan, P., Yokomaku, D., Hamdan, F. F., Champagne, N., Lapointe, M., Spiegelman, D., Noreau, A., Lafrenière, R. G., et al. (2011) · Human Genetics · doi:10.1007/s00439-011-0975-z · Cited by 286 · see citing works
SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1
Iijima, T., Wu, K., Witte, H., Hanno-Iijima, Y., Glatter, T., Richard, S., & Scheiffele, P. (2011) · Cell · doi:10.1016/j.cell.2011.11.028 · Cited by 279 · see citing works
Missler, M., Sudhof, T. C., & Biederer, T. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005694 · Cited by 255 · see citing works
The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins
Bolliger, M. F., Martinelli, D. C., & Südhof, T. C. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019577108 · Cited by 189 · see citing works
Self-citationTranssynaptic modulation of kainate receptor functions by C1q-like proteins
Matsuda, K., Budisantoso, T., Mitakidis, N., Sugaya, Y., Miura, E., Kakegawa, W., Yamasaki, M., Konno, K., Uchigashima, M., Abe, M., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.001 · Cited by 180 · see citing works
Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development
Quesnel-Vallières, M., Irimia, M., Cordes, S. P., & Blencowe, B. J. (2015) · Genes & Development · doi:10.1101/gad.256115.114 · Cited by 155 · see citing works
Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J., & Südhof, T. C. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.182 · Cited by 140 · see citing works
Self-citationPolarized targeting of neurexins to synapses is regulated by their C-terminal sequences
Fairless, R., Masius, H., Rohlmann, A., Heupel, K., Ahmad, M., Reissner, C., Dresbach, T., & Missler, M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.5294-07.2008 · Cited by 91 · see citing works
Deletion of α‐neurexins does not cause a major impairment of axonal pathfinding or synapse formation
Dudanova, I., Tabuchi, K., Rohlmann, A., Südhof, T. C., & Missler, M. (2007) · Journal of Comparative Neurology · doi:10.1002/cne.21305 · Cited by 98 · see citing works
Self-citationChoi, Y.-B., Li, H.-L., Kassabov, S. R., Jin, I., Puthanveettil, S. V., Karl, K. A., Lu, Y., Kim, J.-H., Bailey, C. H., & Kandel, E. R. (2011) · Neuron · doi:10.1016/j.neuron.2011.03.020 · Cited by 94 · see citing works
Neuronal cell type–specific alternative splicing is regulated by the KH domain protein SLM1
Iijima, T., Iijima, Y., Witte, H., & Scheiffele, P. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201310136 · Cited by 90 · see citing works
Hunter, J. W., Mullen, G. P., McManus, J. R., Heatherly, J. M., Duke, A., & Rand, J. B. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.003442 · Cited by 86 · see citing works
Ehrmann, I., Dalgliesh, C., Liu, Y., Danilenko, M., Crosier, M., Overman, L., Arthur, H. M., Lindsay, S., Clowry, G. J., Venables, J. P., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003474 · Cited by 82 · see citing works
Traunmüller, L., Bornmann, C., & Scheiffele, P. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.3395-14.2014 · Cited by 40 · see citing works
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Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity
Lee, A. K., Khaled, H., Chofflet, N., & Takahashi, H. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00281 · Cited by 14 · see citing works
- Authors
- Boucard, A. A., Chubykin, A. A., Comoletti, D., Taylor, P., & Südhof, T. C.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Südhof, Thomas C.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 48
- Issue
- 2
- Pages
- 229-236
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1990122129
- Cited by
- 470
- References
- 30
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 13 · 2023: 13 · 2022: 13 · 2021: 29 · 2020: 21 · 2019: 15 · 2018: 11 · 2017: 16 · 2016: 23 · 2015: 25 · 2014: 26 · 2013: 22 · 2012: 24
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R37-MH52804-08, R37MH052804)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- neuroligin-1, neurexin, alternative splicing, synaptogenesis
- MeSH terms
- Animals, Animals, Newborn, Cell Adhesion, Cells, Cultured, Chromatography, Affinity, Glycoproteins, Hippocampus, Humans, Immunohistochemistry, Membrane Proteins, Microtubule-Associated Proteins, Nerve Tissue Proteins, Neurons, Neuropeptides, Protein Binding, Recombinant Proteins, Synapses, Transfection, Blotting, Western, Cell Adhesion Molecules, Neuronal, Mutagenesis, Synapsins, Alternative Splicing, Electrophoretic Mobility Shift Assay, Green Fluorescent Proteins, Rats
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