Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity

Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated by neuroligin-1. We propose that the A1 insert could be a target for alleviating the consequences of deleterious NLGN1/3 mutations, supported by assays with the autism-linked neuroligin-1-P89L mutant. An enrichment of neuroligin-1 A1 in GABAergic neuron types suggests a role in synchrony of cortical circuits. Altogether, these data reveal an unusual mode by which neuroligin splicing controls synapse development through protein-glycan interaction and identify it as a potential therapeutic target.

[1]  Masahiko Watanabe,et al.  Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus , 2020, The Journal of Biological Chemistry.

[2]  O. Thoumine,et al.  Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation , 2019, bioRxiv.

[3]  Steven A. Connor,et al.  Pumping the brakes: suppression of synapse development by MDGA–neuroligin interactions , 2019, Current Opinion in Neurobiology.

[4]  M. Shaw,et al.  Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment , 2019, Human mutation.

[5]  P. Scheiffele,et al.  Landscape of ribosome-engaged transcript isoforms reveals extensive neuronal cell class-specific alternative splicing programs , 2019, Nature Neuroscience.

[6]  A. Krainer,et al.  Antisense Oligonucleotide Therapies for Neurodegenerative Diseases. , 2019, Annual review of neuroscience.

[7]  Francisco J Luongo,et al.  VIP Interneurons Contribute to Avoidance Behavior by Regulating Information Flow across Hippocampal-Prefrontal Networks , 2019, Neuron.

[8]  K. Roche,et al.  PSD-95 binding dynamically regulates NLGN1 trafficking and function , 2019, Proceedings of the National Academy of Sciences.

[9]  Zhengping Jia,et al.  Regulation of hippocampal long term depression by Neuroligin 1 , 2018, Neuropharmacology.

[10]  O. Thoumine,et al.  A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation , 2018, Nature Communications.

[11]  M. Botella,et al.  A novel nonsense homozygous variant in the NLGN1 gene found in a pair of monozygotic twin brothers with intellectual disability and autism , 2018, Clinical genetics.

[12]  Kenji F. Tanaka,et al.  Heparan Sulfate Organizes Neuronal Synapses through Neurexin Partnerships , 2018, Cell.

[13]  Mingjie Zhang,et al.  Reconstituted Postsynaptic Density as a Molecular Platform for Understanding Synapse Formation and Plasticity , 2018, Cell.

[14]  D. Black,et al.  Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1 , 2018, Neuron.

[15]  Jun Xia,et al.  Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice , 2018, Neuron.

[16]  Sebastien M. Weyn-Vanhentenryck,et al.  Rbfox Splicing Factors Promote Neuronal Maturation and Axon Initial Segment Assembly , 2018, Neuron.

[17]  L. Mei,et al.  Neuromuscular Junction Formation, Aging, and Disorders. , 2018, Annual review of physiology.

[18]  Sebastien M. Weyn-Vanhentenryck,et al.  Precise temporal regulation of alternative splicing during neural development , 2018, bioRxiv.

[19]  Allan R. Jones,et al.  Shared and distinct transcriptomic cell types across neocortical areas , 2017, bioRxiv.

[20]  T. Südhof,et al.  Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits , 2017, Cell.

[21]  M. Bucan,et al.  Functional significance of rare neuroligin 1 variants found in autism , 2017, PLoS genetics.

[22]  K. Roche,et al.  Posttranslational modifications of neuroligins regulate neuronal and glial signaling , 2017, Current Opinion in Neurobiology.

[23]  A. Craig,et al.  Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins , 2017, Neuron.

[24]  E. Androphy,et al.  How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy , 2017, Gene Therapy.

[25]  T. Südhof,et al.  Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network , 2016, Nature Neuroscience.

[26]  S. Scherer,et al.  Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation , 2016, Journal of Neurodevelopmental Disorders.

[27]  Douglas W. Woods,et al.  Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome , 2016, Neuron.

[28]  T. Südhof,et al.  Conditional ablation of neuroligin-1 in CA1 pyramidal neurons blocks LTP by a cell-autonomous NMDA receptor-independent mechanism , 2016, Molecular Psychiatry.

[29]  P. Scheiffele,et al.  Control of neuronal synapse specification by a highly dedicated alternative splicing program , 2016, Science.

[30]  D. Black,et al.  The neurogenetics of alternative splicing , 2016, Nature Reviews Neuroscience.

[31]  O. Thoumine,et al.  Mapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin , 2016, Nature Communications.

[32]  Sisi Jiang,et al.  Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population , 2015, PloS one.

[33]  Benjamin J. Blencowe,et al.  Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles , 2015, Neuron.

[34]  Sebastien M. Weyn-Vanhentenryck,et al.  Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators , 2015, Proceedings of the National Academy of Sciences.

[35]  G. Kirov,et al.  Analysis of copy number variations at 15 schizophrenia-associated loci , 2014, The British journal of psychiatry : the journal of mental science.

[36]  D. Black,et al.  The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation , 2014, eLife.

[37]  T. Südhof,et al.  Membrane-Tethered Monomeric Neurexin LNS-Domain Triggers Synapse Formation , 2013, The Journal of Neuroscience.

[38]  Matthew D. Schultz,et al.  Global Epigenomic Reconfiguration During Mammalian Brain Development , 2013, Science.

[39]  Weiwei Zhao.  Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations , 2013, Molecular Cytogenetics.

[40]  Michael Q. Zhang,et al.  OLego: fast and sensitive mapping of spliced mRNA-Seq reads using small seeds , 2013, Nucleic acids research.

[41]  Jung Hoon Jung,et al.  Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling , 2012, Proceedings of the National Academy of Sciences.

[42]  B. Sabatini,et al.  Neuroligin-1–dependent competition regulates cortical synaptogenesis and synapse number , 2012, Nature Neuroscience.

[43]  R. Nicoll,et al.  A Subtype-Specific Function for the Extracellular Domain of Neuroligin 1 in Hippocampal LTP , 2012, Neuron.

[44]  B. Sabatini,et al.  Cortical synaptogenesis and excitatory synapse number are determined via a Neuroligin-1-dependent intercellular competition , 2012, Nature Neuroscience.

[45]  M. Ares,et al.  Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy , 2012, Neuron.

[46]  J. Takagi,et al.  Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules neurexin and neuroligin. , 2012, Cell reports.

[47]  Bradley P. Coe,et al.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations , 2012, Nature.

[48]  O. Thoumine,et al.  Neurexin-Neuroligin Adhesions Capture Surface-Diffusing AMPA Receptors through PSD-95 Scaffolds , 2011, The Journal of Neuroscience.

[49]  T. Murphy,et al.  Postsynaptic TrkC and Presynaptic PTPσ Function as a Bidirectional Excitatory Synaptic Organizing Complex , 2011, Neuron.

[50]  D. Zack,et al.  Alternative splicing of neuroligin and its protein distribution in the outer plexiform layer of the chicken retina , 2010, The Journal of comparative neurology.

[51]  B. Honig,et al.  Splice Form Dependence of β-Neurexin/Neuroligin Binding Interactions , 2010, Neuron.

[52]  Raika Pancaroglu,et al.  LRRTMs and Neuroligins Bind Neurexins with a Differential Code to Cooperate in Glutamate Synapse Development , 2010, The Journal of Neuroscience.

[53]  T. Dresbach,et al.  Essential cooperation of N-cadherin and neuroligin-1 in the transsynaptic control of vesicle accumulation , 2010, Proceedings of the National Academy of Sciences.

[54]  T. Südhof,et al.  Neuroligin-1 Deletion Results in Impaired Spatial Memory and Increased Repetitive Behavior , 2010, The Journal of Neuroscience.

[55]  M. Beltrame,et al.  Characterization of the neuroligin gene family expression and evolution in zebrafish , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[56]  T. Südhof,et al.  Neuroligin‐1 performs neurexin‐dependent and neurexin‐independent functions in synapse validation , 2009, The EMBO journal.

[57]  Robert T. Schultz,et al.  Autism genome-wide copy number variation reveals ubiquitin and neuronal genes , 2009, Nature.

[58]  N. Grishin,et al.  Unusually rapid evolution of Neuroligin-4 in mice , 2008, Proceedings of the National Academy of Sciences.

[59]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[60]  Tsutomu Hashikawa,et al.  Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95–neuroligin , 2007, Nature Neuroscience.

[61]  S. Kaech,et al.  Culturing hippocampal neurons , 2006, Nature Protocols.

[62]  Borries Demeler,et al.  Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. , 2006, Biochemistry.

[63]  Thomas C. Südhof,et al.  Neuroligins Determine Synapse Maturation and Function , 2006, Neuron.

[64]  P. Scheiffele,et al.  Alternative Splicing Controls Selective Trans-Synaptic Interactions of the Neuroligin-Neurexin Complex , 2006, Neuron.

[65]  Pieter C Dorrestein,et al.  A monovalent streptavidin with a single femtomolar biotin binding site , 2006, Nature Methods.

[66]  Thomas C. Südhof,et al.  A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins , 2005, Neuron.

[67]  Ann Marie Craig,et al.  Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins , 2004, Cell.

[68]  I. Tsigelny,et al.  Structural characterization of recombinant soluble rat neuroligin 1: mapping of secondary structure and glycosylation by mass spectrometry. , 2004, Biochemistry.

[69]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[70]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[71]  R. Fetter,et al.  Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons , 2000, Cell.

[72]  J. Sanes,et al.  Alternatively Spliced Isoforms of Nerve- and Muscle-Derived Agrin Their Roles at the Neuromuscular Junction , 1999, Neuron.

[73]  J. Fallon,et al.  Alternative splicing of agrin regulates its binding to heparin alpha-dystroglycan, and the cell surface. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[74]  M. Ruegg,et al.  Alternative Splicing of Agrin Alters Its Binding to Heparin, Dystroglycan, and the Putative Agrin Receptor , 1996, Neuron.

[75]  Xing Chen,et al.  A novel relationship for schizophrenia, bipolar and major depressive disorder Part 3: Evidence from chromosome 3 high density association screen , 2018, The Journal of comparative neurology.

[76]  E. Androphy,et al.  How the discovery of ISSN 1 led to the first medical therapy for spinal muscular atrophy , 2017 .