Regulation and postsynaptic binding of neurexins – drug targets for neurodevelopmental and neuropsychiatric disorders

Yicheng Ding1,Linda Howard1,Louise Gallagher2,Sanbing Shen1,*()

PDF(498 KB)
PDF(498 KB)
Front. Biol. ›› 2015, Vol. 10 ›› Issue (3) : 239-251. DOI: 10.1007/s11515-015-1363-1
REVIEW

Regulation and postsynaptic binding of neurexins – drug targets for neurodevelopmental and neuropsychiatric disorders

  • Yicheng Ding1,Linda Howard1,Louise Gallagher2,Sanbing Shen1,*()
Author information +
History +

Abstract

Neurexins (NRXNs) have been linked to neurodevelopmental and neuropsychiatric disorders and have become attractive drug targets. They are transmembrane neuronal adhesion molecules and play important roles in the formation and differentiation of synapses and synaptic activity. Many postsynaptic binding partners of NRXNs have been identified. The interactions between NRXNs and postsynaptic binding partners can be regulated by alternative splicing, synaptic activity, and RNA binding proteins. The postsynaptic interactive partners may compete with each other for NRXN binding. The expression of NRXNs can also be regulated transcriptionally and post-transcriptionally. Genetic polymorphism may affect the function and expression of NRXNs. In this review, we will summarize the recent advance in these areas. Understanding the biology of neurexin signaling is essential for developing neurexin-based drugs.

Keywords

alternative splicing / neurexins / neurodevelopmental disorders / neuropsychiatric illness / post-synaptic interactive partners / regulation / synapse

Cite this article

Download citation ▾
Yicheng Ding,Linda Howard,Louise Gallagher,Sanbing Shen. Regulation and postsynaptic binding of neurexins – drug targets for neurodevelopmental and neuropsychiatric disorders. Front. Biol., 2015, 10(3): 239‒251 https://doi.org/10.1007/s11515-015-1363-1

References

1 <?Pub Caret?> Aoto J, Martinelli D C, Malenka R C, Tabuchi K, Südhof T C (2013). Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell, 154(1): 75–88
2 Bang M L, Owczarek S (2013). A matter of balance: role of neurexin and neuroligin at the synapse. Neurochem Res, 38(6): 1174–1189
3 Batista-Brito R, Machold R, Klein C, Fishell G (2008). Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb Cortex, 18(10): 2306–2317
4 Beglopoulos V, Montag-Sallaz M, Rohlmann A, Piechotta K, Ahmad M, Montag D, Missler M (2005). Neurexophilin 3 is highly localized in cortical and cerebellar regions and is functionally important for sensorimotor gating and motor coordination. Mol Cell Biol, 25(16): 7278–7288
5 Béna F, Bruno D L, Eriksson M, van Ravenswaaij-Arts C, Stark Z, Dijkhuizen T, Gerkes E, Gimelli S, Ganesamoorthy D, Thuresson A C, Labalme A, Till M, Bilan F, Pasquier L, Kitzis A, Dubourgm C, Rossi M, Bottani A, Gagnebin M, Sanlaville D, Gilbert-Dussardier B, Guipponi M, van Haeringen A, Kriek M, Ruivenkamp C, Antonarakis S E, Anderlid B M, Slater H R, Schoumans J (2013). Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am J Med Genet B Neuropsychiatr Genet, 162B(4): 388–403
6 Biederer T, Sudhof T C (2001). CASK and protein 4.1 support F-actin nucleation on neurexins. J Biol Chem, 276(51): 47869–47876
7 Blundell J, Blaiss C A, Etherton M R, Espinosa F, Tabuchi K, Walz C, Bolliger M F, Südhof T C, Powell C M (2010). Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci, 30(6): 2115–2129
8 Bolliger M F, Frei K, Winterhalter K H, Gloor S M (2001). Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. Biochem J, 356(Pt 2): 581–588
9 Borg J P, Straight S W, Kaech S M, de Taddéo-Borg M, Kroon D E, Karnak D, Turner R S, Kim S K, Margolis B (1998). Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting. J Biol Chem, 273(48): 31633–31636
10 Born G, Breuer D, Wang S, Rohlmann A, Coulon P, Vakili P, Reissner C, Kiefer F, Heine M, Pape H C, Missler M (2014). Modulation of synaptic function through the α-neurexin-specific ligand neurexophilin-1. Proc Natl Acad Sci USA, 111(13): E1274–E1283
11 Boucard A A, Chubykin A A, Comoletti D, Taylor P, Südhof T C (2005). A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins. Neuron, 48(2): 229–236
12 Boucard A A, Ko J, Südhof T C (2012). High affinity neurexin binding to cell adhesion G-protein-coupled receptor CIRL1/latrophilin-1 produces an intercellular adhesion complex. J Biol Chem, 287(12): 9399–9413
13 Bourne Y, Marchot P (2014). The neuroligins and their ligands: from structure to function at the synapse. J Mol Neurosci, 53(3): 387–396
14 Briatore F, Patrizi A, Viltono L, Sassoè-Pognetto M, Wulff P (2010). Quantitative organization of GABAergic synapses in the molecular layer of the mouse cerebellar cortex. PLoS ONE, 5(8): e12119
15 Bucan M, Abrahams B S, Wang K, Glessner J T, Herman E I, Sonnenblick L I, Alvarez Retuerto A I, Imielinski M, Hadley D, Bradfield J P, Kim C, Gidaya N B, Lindquist I, Hutman T, Sigman M, Kustanovich V, Lajonchere C M, Singleton A, Kim J, Wassink T H, McMahon W M, Owley T, Sweeney J A, Coon H, Nurnberger J I, Li M, Cantor R M, Minshew N J, Sutcliffe J S, Cook E H, Dawson G, Buxbaum J D, Grant S F, Schellenberg G D, Geschwind D H, Hakonarson H (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet, 5(6): e1000536
16 Budreck E C, Scheiffele P (2007). Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur J Neurosci, 26(7): 1738–1748
17 Butz S, Okamoto M, Südhof T C (1998). A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell, 94(6): 773–782
18 Camacho-Garcia R J, Planelles M I, Margalef M, Pecero M L, Martínez-Leal R, Aguilera F, Vilella E, Martinez-Mir A, Scholl F G (2012). Mutations affecting synaptic levels of neurexin-1β in autism and mental retardation. Neurobiol Dis, 47(1): 135–143
19 Chahrour M, Jung S Y, Shaw C, Zhou X, Wong S T, Qin J, Zoghbi H Y (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science, 320(5880): 1224–1229
20 Chih B, Gollan L, Scheiffele P (2006). Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron, 51(2): 171–178
21 Ching M S, Shen Y, Tan W H, Jeste S S, Morrow E M, Chen X, Mukaddes N M, Yoo S Y, Hanson E, Hundley R, Austin C, Becker R E, Berry G T, Driscoll K, Engle E C, Friedman S, Gusella J F, Hisama F M, Irons M B, Lafiosca T, LeClair E, Miller D T, Neessen M, Picker J D, Rappaport L, Rooney C M, Sarco D P, Stoler J M, Walsh C A, Wolff R R, Zhang T, Nasir R H, Wu B L, and the Children’s Hospital Boston Genotype Phenotype Study Group (2010). Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet, 153B(4): 937–947
22 Comoletti D, De Jaco A, Jennings L L, Flynn R E, Gaietta G, Tsigelny I, Ellisman M H, Taylor P (2004). The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci, 24(20): 4889–4893
23 Craig A M, Kang Y (2007). Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol, 17(1): 43–52
24 Curran S, Ahn J W, Grayton H, Collier D A, Ogilvie C M (2013). NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series- further understanding of the relevance of NRXN1 to neurodevelopmental disorders. J Mol Psychiatry, 1(1): 4
25 Dean C, Dresbach T (2006). Neuroligins and neurexins: linking cell adhesion, synapse formation and cognitive function. Trends Neurosci, 29(1): 21–29
26 Dean C, Scholl F G, Choih J, DeMaria S, Berger J, Isacoff E, Scheiffele P (2003). Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci, 6(7): 708–716
27 Di Fruscio M, Chen T, Richard S (1999). Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc Natl Acad Sci USA, 96(6): 2710–2715
28 Duong L, Klitten L L, M?ller R S, Ingason A, Jakobsen K D, Skj?dt C, Didriksen M, Hjalgrim H, Werge T, Tommerup N (2012). Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. Am J Med Genet B Neuropsychiatr Genet, 159B(3): 354–358
29 Ehrmann I, Dalgliesh C, Liu Y, Danilenko M, Crosier M, Overman L, Arthur H M, Lindsay S, Clowry G J, Venables J P, Fort P, Elliott D J (2013). The tissue-specific RNA binding protein T-STAR controls regional splicing patterns of neurexin pre-mRNAs in the brain. PLoS Genet, 9(4): e1003474
30 Etherton M R, Blaiss C A, Powell C M, Südhof T C (2009). Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc Natl Acad Sci USA, 106(42): 17998–18003
31 Fan Z, Chen X, Chen R (2014). Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression. Genomics, 103(1): 76–82
32 Fang Z H, Lee C H, Seo M K, Cho H, Lee J G, Lee B J, Park S W, Kim Y H (2013). Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats. Neurosci Res, 76(4): 187–194
33 Feng J, Schroer R, Yan J, Song W, Yang C, Bockholt A, Cook E H Jr, Skinner C, Schwartz C E, Sommer S S (2006). High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett, 409(1): 10–13
34 Fu Y, Huang Z J (2010). Differential dynamics and activity-dependent regulation of alpha- and beta-neurexins at developing GABAergic synapses. Proc Natl Acad Sci USA, 107(52): 22699–22704
35 Gauthier J, Siddiqui T J, Huashan P, Yokomaku D, Hamdan F F, Champagne N, Lapointe M, Spiegelman D, Noreau A, Lafrenière R G, Fathalli F, Joober R, Krebs M O, DeLisi L E, Mottron L, Fombonne E, Michaud J L, Drapeau P, Carbonetto S, Craig A M, Rouleau G A (2011). Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet, 130(4): 563–573
36 Glessner J T, Wang K, Cai G, Korvatska O, Kim C E, Wood S, Zhang H, Estes A, Brune C W, Bradfield J P, Imielinski Glessner J T, Wang K, Cai G, Korvatska O, Kim C E, Wood S, Zhang H, Estes A, Brune C W, Bradfield J P, Imielinski M, Frackelton E C, Reichert J, Crawford E L, Munson J, Sleiman P M, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer K J, Anagnostou E, Sakurai T, Game R M, Rudd D S, Zurawiecki D, McDougle C J, Davis L K, Miller J, Posey D J, Michaels S, Kolevzon A, Silverman J M, Bernier R, Levy S E, Schultz R T, Dawson G, Owley T, McMahon W M, Wassink T H, Sweeney J A, Nurnberger J I, Coon H, Sutcliffe J S, Minshew N J, Grant S F, Bucan M, Cook E H, Buxbaum J D, Devlin B, Schellenberg G D, Hakonarson H (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459(7246): 569–573
37 Graf E R, Kang Y, Hauner A M, Craig A M (2006). Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain. J Neurosci, 26(16): 4256–4265
38 Graf E R, Zhang X, Jin S X, Linhoff M W, Craig A M (2004). Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell, 119(7): 1013–1026
39 Grayton H M, Missler M, Collier D A, Fernandes C (2013). Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders. PLoS ONE, 8(6): e67114
40 Gunn B G, Cunningham L, Mitchell S G, Swinny J D, Lambert J J, Belelli D ( 2014). GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response. Front Neuroendocrinol, 36: 28–48
41 Hata Y, Butz S, Südhof T C (1996). CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci, 16(8): 2488–2494
42 Hemler M E (1999). Dystroglycan versatility. Cell, 97(5): 543–546
43 Henry M D, Campbell K P (1998). A role for dystroglycan in basement membrane assembly. Cell, 95(6): 859–870
44 Henry M D, Campbell K P (1999). Dystroglycan inside and out. Curr Opin Cell Biol, 11(5): 602–607
45 Hines R M, Wu L, Hines D J, Steenland H, Mansour S, Dahlhaus R, Singaraja R R, Cao X, Sammler E, Hormuzdi S G, Zhuo M, El-Husseini A (2008). Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression. J Neurosci, 28(24): 6055–6067
46 Hirai H, Pang Z, Bao D, Miyazaki T, Li L, Miura E, Parris J, Rong Y, Watanabe M, Yuzaki M, Morgan J I (2005). Cbln1 is essential for synaptic integrity and plasticity in the cerebellum. Nat Neurosci, 8(11): 1534–1541
47 Hoon M, Soykan T, Falkenburger B, Hammer M, Patrizi A, Schmidt K F, Sassoè-Pognetto M, L?wel S, Moser T, Taschenberger H, Brose N, Varoqueaux F (2011). Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina. Proc Natl Acad Sci USA, 108(7): 3053–3058
48 Ibraghimov-Beskrovnaya O, Ervasti J M, Leveille C J, Slaughter C A, Sernett S W, Campbell K P, Campbel K P (1992). Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature, 355(6362): 696–702
49 Ichtchenko K, Hata Y, Nguyen T, Ullrich B, Missler M, Moomaw C, Südhof T C (1995). Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell, 81(3): 435–443
50 Iijima T, Iijima Y, Witte H, Scheiffele P (2014). Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1. J Cell Biol, 204(3): 331–342
51 Iijima T, Wu K, Witte H, Hanno-Iijima Y, Glatter T, Richard S, Scheiffele P (2011). SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell, 147(7): 1601–1614
52 Jamain S, Quach H, Betancur C, R?stam M, Colineaux C, Gillberg I C, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T, Gillberg C, R?stam M, Gillberg C, Nydén A, S?derstr?m H, Leboyer M, Betancur C, Philippe A, Giros B, Colineaux C, Cohen D, Chabane N, Mouren-Siméoni M C, Brice A, Sponheim E, Spurkland I, Skjeldal O H, Coleman M, Pearl P L, Cohen I L, Tsiouris J, Zappella M, Menchetti G, Pompella A, Aschauer H, Van Maldergem L, the Paris Autism Research International Sibpair Study (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet, 34(1): 27–29
53 Jamain S, Radyushkin K, Hammerschmidt K, Granon S, Boretius S, Varoqueaux F, Ramanantsoa N, Gallego J, Ronnenberg A, Winter D, Frahm J, Fischer J, Bourgeron T, Ehrenreich H, Brose N (2008). Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA, 105(5): 1710–1715
54 Kang H S, Lee C K, Kim J R, Yu S J, Kang S G, Moon D H, Lee C H, Kim D K (2004). Gene expression analysis of the pro-oestrous-stage rat uterus reveals neuroligin 2 as a novel steroid-regulated gene. Reprod Fertil Dev, 16(8): 763–772
55 Kang Y, Zhang X, Dobie F, Wu H, Craig A M (2008). Induction of GABAergic postsynaptic differentiation by alpha-neurexins. J Biol Chem, 283(4): 2323–2334
56 Kattenstroth G, Tantalaki E, Südhof T C, Gottmann K, Missler M (2004). Postsynaptic N-methyl-D-aspartate receptor function requires alpha-neurexins. Proc Natl Acad Sci USA, 101(8): 2607–2612
57 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, Descartes M, Holt L, Braddock S, Troxell R, Kaplan L, Volkmar F, Klin A, Tsatsanis K, Harris D J, Noens I, Pauls D L, Daly M J, MacDonald M E, Morton C C, Quade B J, Gusella J F (2008). Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet, 82(1): 199–207
58 Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O’Donovan M C, Erdogan F, Owen M J, Ropers H H, Ullmann R (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet, 17(3): 458–465
59 Kirov G, Rujescu D, Ingason A, Collier D A, O’Donovan M C, Owen M J (2009). Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull, 35(5): 851–854
60 Ko J, Fuccillo M V, Malenka R C, Südhof T C (2009). LRRTM2 functions as a neurexin ligand in promoting excitatory synapse formation. Neuron, 64(6): 791–798
61 Ko J, Soler-Llavina G J, Fuccillo M V, Malenka R C, Südhof T C (2011). Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons. J Cell Biol, 194(2): 323–334
62 Krueger D D, Tuffy L P, Papadopoulos T, Brose N (2012). The role of neurexins and neuroligins in the formation, maturation, and function of vertebrate synapses. Curr Opin Neurobiol, 22(3): 412–422
63 Kwon H B, Kozorovitskiy Y, Oh W J, Peixoto R T, Akhtar N, Saulnier J L, Gu C, Sabatini B L (2012). Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number. Nat Neurosci, 15(12): 1667–1674
64 Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard M P, Raynaud M, Ronce N, Lemonnier E, Calvas P, Laudier B, Chelly J, Fryns J P, Ropers H H, Hamel B C, Andres C, Barthélémy C, Moraine C, Briault S (2004). X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet, 74(3): 552–557
65 Laurén J, Airaksinen M S, Saarma M, Timmusk T (2003). A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics, 81(4): 411–421
66 Lawson-Yuen A, Saldivar J S, Sommer S, Picker J (2008). Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet, 16(5): 614–618
67 Lévi S, Grady R M, Henry M D, Campbell K P, Sanes J R, Craig A M (2002). Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation. J Neurosci, 22(11): 4274–4285
68 Levinson J N, El-Husseini A (2005). Building excitatory and inhibitory synapses: balancing neuroligin partnerships. Neuron, 48(2): 171–174
69 Linhoff M W, Laurén J, Cassidy R M, Dobie F A, Takahashi H, Nygaard H B, Airaksinen M S, Strittmatter S M, Craig A M (2009). An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron, 61(5): 734–749
70 Lisé M F, El-Husseini A (2006). The neuroligin and neurexin families: from structure to function at the synapse. Cell Mol Life Sci, 63(16): 1833–1849
71 Liu Y, Hu Z, Xun G, Peng Y, Lu L, Xu X, Xiong Z, Xia L, Liu D, Li W, Zhao J, Xia K (2012). Mutation analysis of the NRXN1 gene in a Chinese autism cohort. J Psychiatr Res, 46(5): 630–634
72 Matsuda K, Miura E, Miyazaki T, Kakegawa W, Emi K, Narumi S, Fukazawa Y, Ito-Ishida A, Kondo T, Shigemoto R, Watanabe M, Yuzaki M (2010). Cbln1 is a ligand for an orphan glutamate receptor delta2, a bidirectional synapse organizer. Science, 328(5976): 363–368
73 Matsuda K, Yuzaki M (2011). Cbln family proteins promote synapse formation by regulating distinct neurexin signaling pathways in various brain regions. Eur J Neurosci, 33(8): 1447–1461
74 Millson A, Lagrave D, Willis M J, Rowe L R, Lyon E, South S T (2012). Chromosomal loss of 3q26.3-3q26.32, involving a partial neuroligin 1 deletion, identified by genomic microarray in a child with microcephaly, seizure disorder, and severe intellectual disability. Am J Med Genet A, 158A(1): 159–165
75 Missler M, Fernandez-Chacon R, Südhof T C (1998a). The making of neurexins. J Neurochem, 71(4): 1339–1347
76 Missler M, Hammer R E, Südhof T C (1998b). Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit. J Biol Chem, 273(52): 34716–34723
77 Missler M, Südhof T C (1998). Neurexophilins form a conserved family of neuropeptide-like glycoproteins. J Neurosci, 18(10): 3630–3638
78 Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer R E, Gottmann K, Südhof T C (2003). α-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature, 423(6943): 939–948
79 Mukherjee K, Sharma M, Urlaub H, Bourenkov G P, Jahn R, Südhof T C, Wahl M C (2008). CASK Functions as a Mg2+-independent neurexin kinase. Cell, 133(2): 328–339
80 Nam C I, Chen L (2005). Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter. Proc Natl Acad Sci USA, 102(17): 6137–6142
81 O’Dushlaine C, Kenny E, Heron E, Donohoe G, Gill M, Morris D, Corvin A, and the International Schizophrenia Consortium (2011). Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol Psychiatry, 16(3): 286–292
82 Petrenko A G, Ullrich B, Missler M, Krasnoperov V, Rosahl T W, Südhof T C (1996). Structure and evolution of neurexophilin. J Neurosci, 16(14): 4360–4369
83 Pettem K L, Yokomaku D, Luo L, Linhoff M W, Prasad T, Connor S A, Siddiqui T J, Kawabe H, Chen F, Zhang L, Rudenko G, Wang Y T, Brose N, Craig A M (2013). The specific α-neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron, 80(1): 113–128
84 Philibert R A, Winfield S L, Sandhu H K, Martin B M, Ginns E I (2000). The structure and expression of the human neuroligin-3 gene. Gene, 246(1-2): 303–310
85 Pregno G, Frola E, Graziano S, Patrizi A, Bussolino F, Arese M, Sassoè-Pognetto M (2013). Differential regulation of neurexin at glutamatergic and GABAergic synapses. Front Cell Neurosci, 7: 35
86 Rabaneda L G, Robles-Lanuza E, Nieto-González J L, Scholl F G (2014). Neurexin dysfunction in adult neurons results in autistic-like behavior in mice. Cell Reports, 8(2): 338–346
87 Reissner C, Runkel F, Missler M (2013). Neurexins. Genome Biol, 14(9): 213
88 Reissner C, Stahn J, Breuer D, Klose M, Pohlentz G, Mormann M, Missler M ( 2014) . Dystroglycan binding to α-neurexin competes with neurexophilin-1 and neuroligin in the brain. J Biol Chem, 289: 27585–27603
89 Rujescu D, Ingason A, Cichon S, Pietil?inen O P, Barnes M R, Toulopoulou T, Picchioni M, Vassos E, Ettinger U, Bramon E, Murray R, Ruggeri M, Tosato S, Bonetto C, Steinberg S, Sigurdsson E, Sigmundsson T, Petursson H, Gylfason A, Olason P I, Hardarsson G, Jonsdottir G A, Gustafsson O, Fossdal R, Giegling I, M?ller H J, Hartmann A M, Hoffmann P, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Djurovic S, Melle I, Andreassen O A, Hansen T, Werge T, Kiemeney L A, Franke B, Veltman J, Buizer-Voskamp J E, Sabatti C, Ophoff R A, Rietschel M, N?then M M, Stefansson K, Peltonen L, St Clair D, Stefansson H, Collier D A, the GROUP Investigators (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet, 18(5): 988–996
90 Runkel F, Rohlmann A, Reissner C, Brand S M, Missler M (2013). Promoter-like sequences regulating transcriptional activity in neurexin and neuroligin genes. J Neurochem, 127(1): 36–47
91 Sassoè-Pognetto M, Frola E, Pregno G, Briatore F, Patrizi A (2011). Understanding the molecular diversity of GABAergic synapses. Front Cell Neurosci, 5: 4
92 Saura C A, Servián-Morilla E, Scholl F G (2011). Presenilin/γ-secretase regulates neurexin processing at synapses. PLoS ONE, 6(4): e19430
93 Siddiqui T J, Pancaroglu R, Kang Y, Rooyakkers A, Craig A M (2010). LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J Neurosci, 30(22): 7495–7506
94 Soler-Llavina G J, Fuccillo M V, Ko J, Südhof T C, Malenka R C (2011). The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo. Proc Natl Acad Sci USA, 108(40): 16502–16509
95 Song J Y, Ichtchenko K, Südhof T C, Brose N (1999). Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci USA, 96(3): 1100–1105
96 Sons M S, Busche N, Strenzke N, Moser T, Ernsberger U, Mooren F C, Zhang W, Ahmad M, Steffens H, Schomburg E D, Plomp J J, Missler M (2006). alpha-Neurexins are required for efficient transmitter release and synaptic homeostasis at the mouse neuromuscular junction. Neuroscience, 138(2): 433–446
97 Suckow A T, Comoletti D, Waldrop M A, Mosedale M, Egodage S, Taylor P, Chessler S D (2008). Expression of neurexin, neuroligin, and their cytoplasmic binding partners in the pancreatic beta-cells and the involvement of neuroligin in insulin secretion. Endocrinology, 149(12): 6006–6017
98 Südhof T C (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature, 455(7215): 903–911
99 Sugita S, Ichtchenko K, Khvotchev M, Südhof T C (1998). alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J Biol Chem, 273(49): 32715–32724
100 Sugita S, Saito F, Tang J, Satz J, Campbell K, Südhof T C (2001). A stoichiometric complex of neurexins and dystroglycan in brain. J Cell Biol, 154(2): 435–445
101 Szatmari P, Paterson A D, Zwaigenbaum L, Roberts W, Brian J, Liu X Q, Vincent J B, Skaug J L, Thompson A P, Senman L, Feuk L, Qian C, Bryson S E, Jones M B, Marshall C R, Scherer S W, Vieland V J, Bartlett C, Mangin L V, Goedken R, Segre A, Pericak-Vance M A, Cuccaro M L, Gilbert J R, Wright H H, Abramson R K, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum J D, Davis K L, Hollander E, Silverman J M, Hallmayer J, Lotspeich L, Sutcliffe J S, Haines J L, Folstein S E, Piven J, Wassink T H, Sheffield V, Geschwind D H, Bucan M, Brown W T, Cantor R M, Constantino J N, Gilliam T C, Herbert M, Lajonchere C, Ledbetter D H, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse C A, Spence S, State M, Tanzi R E, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon W M, Minshew N, Munson J, Korvatska E, Rodier P M, Schellenberg G D, Smith M, Spence M A, Stodgell C, Tepper P G, Wijsman E M, Yu C E, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck S M, Schuster C, Poustka F, B?lte S, Feineis-Matthews S, Herbrecht E, Schm?tzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal W G, Baird G, Bolton P F, Rutter M L, Weisblatt E, Green J, Aldred C, Wilkinson J A, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey A J, Francis K, Honeyman G, Hutchinson A, Parr J R, Wallace S, Monaco A P, Barnby G, Kobayashi K, Lamb J A, Sousa I, Sykes N, Cook E H, Guter S J, Leventhal B L, Salt J, Lord C, Corsello C, Hus V, Weeks D E, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer K J, the Autism Genome Project Consortium (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet, 39(3): 319–328
102 Tabuchi K, Blundell J, Etherton M R, Hammer R E, Liu X, Powell C M, Südhof T C (2007). A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science, 318(5847): 71–76
103 Tabuchi K, Südhof T C (2002). Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics, 79(6): 849–859
104 Talebizadeh Z, Lam D Y, Theodoro M F, Bittel D C, Lushington G H, Butler M G (2006). Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet, 43(5): e21
105 Tian M, Jacobson C, Gee S H, Campbell K P, Carbonetto S, Jucker M (1996). Dystroglycan in the cerebellum is a laminin alpha 2-chain binding protein at the glial-vascular interface and is expressed in Purkinje cells. Eur J Neurosci, 8(12): 2739–2747
106 Treutlein B, Gokce O, Quake S R, Südhof T C (2014). Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. Proc Natl Acad Sci USA, 111(13): E1291–E1299
107 Uemura T, Lee S J, Yasumura M, Takeuchi T, Yoshida T, Ra M, Taguchi R, Sakimura K, Mishina M (2010). Trans-synaptic interaction of GluRdelta2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell, 141(6): 1068–1079
108 Ullrich B, Ushkaryov Y A, Südhof T C (1995). Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron, 14(3): 497–507
109 Um J W, Pramanik G, Ko J S, Song M Y, Lee D, Kim H, Park K S, Südhof T C, Tabuchi K, Ko J (2014). Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins. Cell Reports, 6(6): 1096–1109
110 Ushkaryov Y A, Petrenko A G, Geppert M, Südhof T C (1992). Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science, 257(5066): 50–56
111 Ushkaryov Y A, Südhof T C (1993). Neurexin III alpha: extensive alternative splicing generates membrane-bound and soluble forms. Proc Natl Acad Sci USA, 90(14): 6410–6414
112 Vaags A K, Lionel A C, Sato D, Goodenberger M, Stein Q P, Curran S, Ogilvie C, Ahn J W, Drmic I, Senman L, Chrysler C, Thompson A, Russell C, Prasad A, Walker S, Pinto D, Marshall C R, Stavropoulos D J, Zwaigenbaum L, Fernandez B A, Fombonne E, Bolton P F, Collier D A, Hodge J C, Roberts W, Szatmari P, Scherer S W (2012). Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet, 90(1): 133–141
113 van der Kooij M A, Fantin M, Kraev I, Korshunova I, Grosse J, Zanoletti O, Guirado R, Garcia-Mompó C, Nacher J, Stewart M G, Berezin V, Sandi C (2014). Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression. Neuropsychopharmacology, 39(5): 1148–1158
114 Varoqueaux F, Aramuni G, Rawson R L, Mohrmann R, Missler M, Gottmann K, Zhang W, Südhof T C, Brose N (2006). Neuroligins determine synapse maturation and function. Neuron, 51(6): 741–754
115 Varoqueaux F, Jamain S, Brose N (2004). Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol, 83(9): 449–456
116 Volk T, Israeli D, Nir R, Toledano-Katchalski H (2008). Tissue development and RNA control: “HOW” is it coordinated? Trends Genet, 24(2): 94–101
117 Waites C L, Craig A M, Garner C C (2005). Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci, 28(1): 251–274
118 Walsh T, McClellan J M, McCarthy S E, Addington A M, Pierce S B, Cooper G M, Nord A S, Kusenda M, Malhotra D, Bhandari A, Stray S M, Rippey C F, Roccanova P, Makarov V, Lakshmi B, Findling R L, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler E E, Meltzer P S, Nelson S F, Singleton A B, Lee M K, Rapoport J L, King M C, Sebat J (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320(5875): 539–543
119 Williams M E, de Wit J, Ghosh A (2010). Molecular mechanisms of synaptic specificity in developing neural circuits. Neuron, 68(1): 9–18
120 Yan J, Feng J, Schroer R, Li W, Skinner C, Schwartz C E, Cook E H Jr, Sommer S S (2008). Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet, 18(4): 204–207
121 Yan J, Noltner K, Feng J, Li W, Schroer R, Skinner C, Zeng W, Schwartz C E, Sommer S S (2008). Neurexin 1alpha structural variants associated with autism. Neurosci Lett, 438(3): 368–370
122 Yan J, Oliveira G, Coutinho A, Yang C, Feng J, Katz C, Sram J, Bockholt A, Jones I R, Craddock N, Cook E H Jr, Vicente A, Sommer S S (2005). Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry, 10(4): 329–332
123 Zhang C, Atasoy D, Ara? D, Yang X, Fucillo M V, Robison A J, Ko J, Brunger A T, Südhof T C (2010). Neurexins physically and functionally interact with GABA(A) receptors. Neuron, 66(3): 403–416
124 Zhang C, Milunsky J M, Newton S, Ko J, Zhao G, Maher T A, Tager-Flusberg H, Bolliger M F, Carter A S, Boucard A A, Powell C M, Südhof T C (2009). A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci, 29(35): 10843–10854
125 Zweier C, de Jong E K, Zweier M, Orrico A, Ousager L B, Collins A L, Bijlsma E K, Oortveld M A, Ekici A B, Reis A, Schenck A, Rauch A (2009). CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet, 85(5): 655–666
PDF(498 KB)

Accesses

Citations

Detail

Sections
Recommended

/