CoChat
Sign Up
Cited by 261Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingGenetics and Neurodevelopmental Disorders

Control of synapse development and plasticity by Rho GTPase regulatory proteins

Open access
Tolias, Kimberley F., Duman, Joseph G., Um, Kyongmi·2011·Progress in Neurobiology
DOI 10.1016/j.pneurobio.2011.04.011PMC PMC3129138
Open this paper in CoChat — free account

Abstract

Synapses are specialized cell-cell contacts that mediate communication between neurons. Most excitatory synapses in the brain are housed on dendritic spines, small actin-rich protrusions extending from dendrites. During development and in response to environmental stimuli, spines undergo marked changes in shape and number thought to underlie processes like learning and memory. Improper spine development, in contrast, likely impedes information processing in the brain, since spine abnormalities are associated with numerous brain disorders. Elucidating the mechanisms that regulate the formation and plasticity of spines and their resident synapses is therefore crucial to our understanding of cognition and disease. Rho-family GTPases, key regulators of the actin cytoskeleton, play essential roles in orchestrating the development and remodeling of spines and synapses. Precise spatio-temporal regulation of Rho GTPase activity is critical for their function, since aberrant Rho GTPase signaling can cause spine and synapse defects as well as cognitive impairments. Rho GTPases are activated by guanine nucleotide exchange factors (GEFs) and inhibited by GTPase-activating proteins (GAPs). We propose that Rho-family GEFs and GAPs provide the spatiotemporal regulation and signaling specificity necessary for proper Rho GTPase function based on the following features they possess: (i) existence of multiple GEFs and GAPs per Rho GTPase, (ii) developmentally regulated expression, (iii) discrete localization, (iv) ability to bind to and organize specific signaling networks, and (v) tightly regulated activity, perhaps involving GEF/GAP interactions. Recent studies describe several Rho-family GEFs and GAPs that uniquely contribute to spinogenesis and synaptogenesis. Here, we highlight several of these proteins and discuss how they occupy distinct biochemical niches critical for synaptic development.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.pneurobio.2011.04.011

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 192

  1. Ahmed S Kozma R Monfries C Hall C Lim HH Smith P Lim L 1990 Human brain n-chimaerin cDNA encodes a novel phorbol ester receptor Biochem J 272 767 773 2268301 PMC1150209
  2. Ahmed S Lee J Kozma R Best A Monfries C Lim L 1993 A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin J Biol Chem 268 10709 10712 8496137
  3. Alexander M Chan KK Byrne AB Selman G Lee T Ono J Wong E Puckrin R Dixon SJ Roy PJ 2009 An UNC-40 pathway directs postsynaptic membrane extension in Caenorhabditis elegans Development 136 911 922 19211675
  4. Allen KM Gleeson JG Bagrodia S Partington MW MacMillan JC Cerione RA Mulley JC Walsh CA 1998 PAK3 mutation in nonsyndromic X-linked mental retardation Nat Genet 20 25 30 9731525
  5. Arimura N Kaibuchi K 2007 Neuronal polarity: from extracellular signals to intracellular mechanisms Nat Rev Neurosci 8 194 205 17311006
  6. Attree O Olivos IM Okabe I Bailey LC Nelson DL Lewis RA McInnes RR Nussbaum RL 1992 The Lowe’s oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase Nature 358 239 242 1321346
  7. Awasaki T Saito M Sone M Suzuki E Sakai R Ito K Hama C 2000 The Drosophila trio plays an essential role in patterning of axons by regulating their directional extension Neuron 26 119 131 10798397
  8. Bagrodia S Taylor SJ Jordon KA Van AL Cerione RA 1998 A novel regulator of p21-activated kinases J Biol Chem 273 23633 23636 9726964
  9. Bateman J Shu H Van Vactor D 2000 The guanine nucleotide exchange factor trio mediates axonal development in the Drosophila embryo Neuron 26 93 106 10798395
  10. Bateman J Van Vactor D 2001 The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance J Cell Sci 114 1973 1980 11493634
  11. Bernards A Settleman J 2004 GAP control: regulating the regulators of small GTPases Trends Cell Biol 14 377 385 15246431
  12. Billuart P Bienvenu T Ronce N des Portes V Vinet MC Zemni R Roest Crollius H Carrie A Fauchereau F Cherry M Briault S Hamel B Fryns JP Beldjord C Kahn A Moraine C Chelly J 1998 Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation Nature 392 923 926 9582072
  13. Billuart P Chelly J 2003 From fragile X mental retardation protein to Rac1 GTPase: new insights from Fly CYFIP Neuron 38 843 845 12818167
  14. Billuart P Winter CG Maresh A Zhao X Luo L 2001 Regulating axon branch stability: the role of p190 RhoGAP in repressing a retraction signaling pathway Cell 107 195 207 11672527
  15. Bourne JN Harris KM 2008 Balancing structure and function at hippocampal dendritic spines Annu Rev Neurosci 31 47 67 18284372 PMC2561948
  16. Bozdagi O Shan W Tanaka H Benson DL Huntley GW 2000 Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation Neuron 28 245 259 11086998
  17. Bozdagi O Valcin M Poskanzer K Tanaka H Benson DL 2004 Temporally distinct demands for classic cadherins in synapse formation and maturation Mol Cell Neurosci 27 509 521 15555928 PMC2910522
  18. Bradley WD Hernandez SE Settleman J Koleske AJ 2006 Integrin signaling through Arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane Mol Biol Cell 17 4827 4836 16971514 PMC1635390
  19. Brouns MR Matheson SF Hu KQ Delalle I Caviness VS Silver J Bronson RT Settleman J 2000 The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development Development 127 4891 4903 11044403
  20. Brouns MR Matheson SF Settleman J 2001 p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation Nat Cell Biol 3 361 367 11283609
  21. Buchsbaum RJ Connolly BA Feig LA 2002 Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade Mol Cell Biol 22 4073 4085 12024021 PMC133864
  22. Buchsbaum RJ Connolly BA Feig LA 2003 Regulation of p70 S6 kinase by complex formation between the Rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin J Biol Chem 278 18833 18841 12531897
  23. Buday L 1999 Membrane-targeting of signalling molecules by SH2/SH3 domain-containing adaptor proteins Biochim Biophys Acta 1422 187 204 10393272
  24. Buttery P Beg AA Chih B Broder A Mason CA Scheiffele P 2006 The diacylglycerol-binding protein alpha1-chimaerin regulates dendritic morphology Proc Natl Acad Sci U S A 103 1924 1929 16446429 PMC1413663
  25. Cahill ME Xie Z Day M Photowala H Barbolina MV Miller CA Weiss C Radulovic J Sweatt JD Disterhoft JF Surmeier DJ Penzes P 2009 Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes Proc Natl Acad Sci U S A 106 13058 13063 19625617 PMC2722269
  26. Caloca MJ Wang H Delemos A Wang S Kazanietz MG 2001 Phorbol esters and related analogs regulate the subcellular localization of beta 2-chimaerin, a non-protein kinase C phorbol ester receptor J Biol Chem 276 18303 18312 11278894
  27. Caloca MJ Wang H Kazanietz MG 2003 Characterization of the Rac-GAP (Rac-GTPase-activating protein) activity of beta2-chimaerin, a ‘non-protein kinase C’ phorbol ester receptor Biochem J 375 313 321 12877655 PMC1223697
  28. Chen X Macara IG 2005 Par-3 controls tight junction assembly through the Rac exchange factor Tiam1 Nat Cell Biol 7 262 269 15723052
  29. Cho YJ Cunnick JM Yi SJ Kaartinen V Groffen J Heisterkamp N 2007 Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages Mol Cell Biol 27 899 911 17116687 PMC1800684
  30. Chuang TH Xu X Kaartinen V Heisterkamp N Groffen J Bokoch GM 1995 Abr and Bcr are multifunctional regulators of the Rho GTP-binding protein family Proc Natl Acad Sci U S A 92 10282 10286 7479768 PMC40780
  31. Cingolani LA Goda Y 2008 Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy Nat Rev Neurosci 9 344 356 18425089
  32. Collins MO Husi H Yu L Brandon JM Anderson CN Blackstock WP Choudhary JS Grant SG 2006 Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome J Neurochem 97 Suppl 1 16 23 16635246
  33. Cull-Candy S Brickley S Farrant M 2001 NMDA receptor subunits: diversity, development and disease Curr Opin Neurobiol 11 327 335 11399431
  34. Dailey ME Smith SJ 1996 The dynamics of dendritic structure in developing hippocampal slices J Neurosci 16 2983 2994 8622128 PMC6579052
  35. Dan B 2009 Angelman syndrome: current understanding and research prospects Epilepsia 50 2331 2339 19874386
  36. DerMardirossian C Bokoch GM 2005 GDIs: central regulatory molecules in Rho GTPase activation Trends Cell Biol 15 356 363 15921909
  37. Diaz E Ge Y Yang YH Loh KC Serafini TA Okazaki Y Hayashizaki Y Speed TP Ngai J Scheiffele P 2002 Molecular analysis of gene expression in the developing pontocerebellar projection system Neuron 36 417 434 12408845
  38. Diekmann D Brill S Garrett MD Totty N Hsuan J Monfries C Hall C Lim L Hall A 1991 Bcr encodes a GTPase-activating protein for p21rac Nature 351 400 402 1903516
  39. Ehler E van LF Collard JG Salinas PC 1997 Expression of Tiam-1 in the developing brain suggests a role for the Tiam-1-Rac signaling pathway in cell migration and neurite outgrowth Mol Cell Neurosci 9 1 12 9204476
  40. Ellis C Moran M McCormick F Pawson T 1990 Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases Nature 343 377 381 1689011
  41. Endris V Wogatzky B Leimer U Bartsch D Zatyka M Latif F Maher ER Tariverdian G Kirsch S Karch D Rappold GA 2002 The novel Rho-GTPase activating gene MEGAP/srGAP3 has a putative role in severe mental retardation Proc Natl Acad Sci U S A 99 11754 11759 12195014 PMC129341
  42. Engert F Bonhoeffer T 1999 Dendritic spine changes associated with hippocampal long-term synaptic plasticity Nature 399 66 70 10331391
  43. Estrach S Schmidt S Diriong S Penna A Blangy A Fort P Debant A 2002 The Human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth Curr Biol 12 307 312 11864571
  44. Ethell IM Irie F Kalo MS Couchman JR Pasquale EB Yamaguchi Y 2001 EphB/syndecan-2 signaling in dendritic spine morphogenesis Neuron 31 1001 1013 11580899
  45. Fauchereau F Herbrand U Chafey P Eberth A Koulakoff A Vinet MC Ahmadian MR Chelly J Billuart P 2003 The RhoGAP activity of OPHN1, a new F-actin-binding protein, is negatively controlled by its amino-terminal domain Mol Cell Neurosci 23 574 586 12932438
  46. Fiala JC Allwardt B Harris KM 2002 Dendritic spines do not split during hippocampal LTP or maturation Nat Neurosci 5 297 298 11896399
  47. Fiala JC Feinberg M Popov V Harris KM 1998 Synaptogenesis via dendritic filopodia in developing hippocampal area CA1 J Neurosci 18 8900 8911 9786995 PMC6793554
  48. Fioretos T Voncken JW Baram TZ Kamme F Groffen J Heisterkamp N 1995 Regional localization and developmental expression of the BCR gene in rodent brain Cell Mol Biol Res 41 97 102 8581068 PMC3791888
  49. Fleming IN Elliott CM Buchanan FG Downes CP Exton JH 1999 Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation J Biol Chem 274 12753 12758 10212259
  50. Forsthoefel DJ Liebl EC Kolodziej PA Seeger MA 2005 The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila Development 132 1983 1994 15790972
  51. Frank CA Pielage J Davis GW 2009 A presynaptic homeostatic signaling system composed of the Eph receptor, ephexin, Cdc42, and CaV2.1 calcium channels Neuron 61 556 569 19249276 PMC2699049
  52. Fu WY Chen Y Sahin M Zhao XS Shi L Bikoff JB Lai KO Yung WH Fu AK Greenberg ME Ip NY 2007 Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism Nat Neurosci 10 67 76 17143272
  53. Gerard A Mertens AE van der Kammen RA Collard JG 2007 The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization J Cell Biol 176 863 875 17353362 PMC2064060
  54. Glaven JA Whitehead I Bagrodia S Kay R Cerione RA 1999 The dbl-related protein, lfc, localizes to microtubules and mediates the activation of rac signaling pathways in cells [In Process Citation] J Biol Chem 274 2279 2285 9890991
  55. Goldstein B Macara IG 2007 The PAR proteins: fundamental players in animal cell polarization Dev Cell 13 609 622 17981131 PMC2964935
  56. Govek EE Newey SE Akerman CJ Cross JR Van der Veken L Van Aelst L 2004 The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis Nat Neurosci 7 364 372 15034583
  57. Govek EE Newey SE Van Aelst L 2005 The role of the Rho GTPases in neuronal development Genes Dev 19 1 49 15630019
  58. Groffen J Heisterkamp N 1997 The chimeric BCR-ABL gene Baillieres Clin Haematol 10 187 201 9376659
  59. Harvey K Duguid IC Alldred MJ Beatty SE Ward H Keep NH Lingenfelter SE Pearce BR Lundgren J Owen MJ Smart TG Luscher B Rees MI Harvey RJ 2004 The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering J Neurosci 24 5816 5826 15215304 PMC6729214
  60. Henkemeyer M Itkis OS Ngo M Hickmott PW Ethell IM 2003 Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus J Cell Biol 163 1313 1326 14691139 PMC1435730
  61. Honkura N Matsuzaki M Noguchi J Ellis-Davies GC Kasai H 2008 The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines Neuron 57 719 729 18341992
  62. Hussain NK Jenna S Glogauer M Quinn CC Wasiak S Guipponi M Antonarakis SE Kay BK Stossel TP Lamarche-Vane N McPherson PS 2001 Endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP Nat Cell Biol 3 927 932 11584276
  63. Irie F Yamaguchi Y 2002 EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP Nat Neurosci 5 1117 1118 12389031
  64. Ishikawa Y Katoh H Negishi M 2003 A role of Rnd1 GTPase in dendritic spine formation in hippocampal neurons J Neurosci 23 11065 11072 14657163 PMC6741061
  65. Jaffe AB Hall A Schmidt A 2005 Association of CNK1 with Rho guanine nucleotide exchange factors controls signaling specificity downstream of Rho Curr Biol 15 405 412 15753034
  66. Jedlicka P Papadopoulos T Deller T Betz H Schwarzacher SW 2009 Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo Mol Cell Neurosci 41 94 100 19236916
  67. Johnson RC Penzes P Eipper BA Mains RE 2000 Isoforms of kalirin, a neuronal Dbl family member, generated through use of different 5′- and 3′-ends along with an internal translational initiation site J Biol Chem 275 19324 19333 10777487
  68. Kaartinen V Gonzalez-Gomez I Voncken JW Haataja L Faure E Nagy A Groffen J Heisterkamp N 2001 Abnormal function of astroglia lacking Abr and Bcr RacGAPs Development 128 4217 4227 11684658
  69. Kaartinen V Nagy A Gonzalez-Gomez I Groffen J Heisterkamp N 2002 Vestibular dysgenesis in mice lacking Abr and Bcr Cdc42/RacGAPs Dev Dyn 223 517 525 11921339
  70. Kasai H Matsuzaki M Noguchi J Yasumatsu N Nakahara H 2003 Structure-stability-function relationships of dendritic spines Trends Neurosci 26 360 368 12850432
  71. Kaufmann WE Moser HW 2000 Dendritic anomalies in disorders associated with mental retardation Cereb Cortex 10 981 991 11007549
  72. Kawauchi T Chihama K Nabeshima Y Hoshino M 2003 The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration Embo J 22 4190 4201 12912917 PMC175802
  73. Kayser MS McClelland AC Hughes EG Dalva MB 2006 Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors J Neurosci 26 12152 12164 17122040 PMC6675446
  74. Kayser MS Nolt MJ Dalva MB 2008 EphB receptors couple dendritic filopodia motility to synapse formation Neuron 59 56 69 18614029 PMC2617787
  75. Khelfaoui M Denis C van Galen E de Bock F Schmitt A Houbron C Morice E Giros B Ramakers G Fagni L Chelly J Nosten-Bertrand M Billuart P 2007 Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity J Neurosci 27 9439 9450 17728457 PMC6673114
  76. Khelfaoui M Pavlowsky A Powell AD Valnegri P Cheong KW Blandin Y Passafaro M Jefferys JG Chelly J Billuart P 2009 Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation Hum Mol Genet 18 2575 2583 19401298 PMC2701329
  77. Kim S Kim T Lee D Park SH Kim H Park D 2000 Molecular cloning of neuronally expressed mouse betaPix isoforms Biochem Biophys Res Commun 272 721 725 10860822
  78. Kim S Ko J Shin H Lee JR Lim C Han JH Altrock WD Garner CC Gundelfinger ED Premont RT Kaang BK Kim E 2003 The GIT family of proteins forms multimers and associates with the presynaptic cytomatrix protein Piccolo J Biol Chem 278 6291 6300 12473661
  79. Kins S Betz H Kirsch J 2000 Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin Nat Neurosci 3 22 29 10607391
  80. Kiraly DD Eipper-Mains JE Mains RE Eipper BA 2010 Synaptic plasticity, a symphony in GEF ACS Chem Neurosci 1 348 365 20543890 PMC2882301
  81. Klein R 2004 Eph/ephrin signaling in morphogenesis, neural development and plasticity Curr Opin Cell Biol 16 580 589 15363810
  82. Klein R 2009 Bidirectional modulation of synaptic functions by Eph/ephrin signaling Nat Neurosci 12 15 20 19029886
  83. Kneussel M Engelkamp D Betz H 2001 Distribution of transcripts for the brain-specific GDP/GTP exchange factor collybistin in the developing mouse brain Eur J Neurosci 13 487 492 11168555
  84. Ko J Kim S Valtschanoff JG Shin H Lee JR Sheng M Premont RT Weinberg RJ Kim E 2003 Interaction between liprin-alpha and GIT1 is required for AMPA receptor targeting J Neurosci 23 1667 1677 12629171 PMC6741975
  85. Koh CG Manser E Zhao ZS Ng CP Lim L 2001 Beta1PIX, the PAK-interacting exchange factor, requires localization via a coiled-coil region to promote microvillus-like structures and membrane ruffles J Cell Sci 114 4239 4251 11739656
  86. Koh TW Verstreken P Bellen HJ 2004 Dap160/intersectin acts as a stabilizing scaffold required for synaptic development and vesicle endocytosis Neuron 43 193 205 15260956
  87. Korus M Mahon GM Cheng L Whitehead IP 2002 p38 MAPK-mediated activation of NF-kappaB by the RhoGEF domain of Bcr Oncogene 21 4601 4612 12096337
  88. Kunda P Paglini G Quiroga S Kosik K Caceres A 2001 Evidence for the involvement of Tiam1 in axon formation J Neurosci 21 2361 2372 11264310 PMC6762399
  89. Kutsche K Yntema H Brandt A Jantke I Nothwang HG Orth U Boavida MG David D Chelly J Fryns JP Moraine C Ropers HH Hamel BC van Bokhoven H Gal A 2000 Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation Nat Genet 26 247 250 11017088
  90. Lambert JM Lambert QT Reuther GW Malliri A Siderovski DP Sondek J Collard JG Der CJ 2002 Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism Nat Cell Biol 4 621 625 12134164
  91. Lamprecht R Farb CR LeDoux JE 2002 Fear memory formation involves p190 RhoGAP and ROCK proteins through a GRB2-mediated complex Neuron 36 727 738 12441060
  92. Lebel RR May M Pouls S Lubs HA Stevenson RE Schwartz CE 2002 Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene Clin Genet 61 139 145 11940089
  93. Leeuwen FN Kain HE Kammen RA Michiels F Kranenburg OW Collard JG 1997 The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho J Cell Biol 139 797 807 9348295 PMC2141700
  94. Lendvai B Stern EA Chen B Svoboda K 2000 Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo Nature 404 876 881 10786794
  95. Leung T How BE Manser E Lim L 1994 Cerebellar beta 2-chimaerin, a GTPase-activating protein for p21 ras- related rac is specifically expressed in granule cells and has a unique N-terminal SH2 domain J Biol Chem 269 12888 12892 8175705
  96. Li J Smithgall TE 1996 Co-expression with BCR induces activation of the FES tyrosine kinase and phosphorylation of specific N-terminal BCR tyrosine residues J Biol Chem 271 32930 32936 8955135
  97. Lim HH Michael GJ Smith P Lim L Hall C 1992 Developmental regulation and neuronal expression of the mRNA of rat n-chimaerin, a p21rac GAP:cDNA sequence Biochem J 287 Pt 2 415 422 1445199 PMC1133181
  98. Linseman DA Loucks FA 2008 Diverse roles of Rho family GTPases in neuronal development, survival, and death Front Biosci 13 657 676 17981578
  99. Lippman J Dunaevsky A 2005 Dendritic spine morphogenesis and plasticity J Neurobiol 64 47 57 15884005
  100. Ma XM Huang J Wang Y Eipper BA Mains RE 2003 Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines J Neurosci 23 10593 10603 14627644 PMC6740925
  101. Ma XM Kiraly DD Gaier ED Wang Y Kim EJ Levine ES Eipper BA Mains RE 2008 Kalirin-7 is required for synaptic structure and function J Neurosci 28 12368 12382 19020030 PMC2586970
  102. MacDonald JF Jackson MF Beazely MA 2006 Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors Crit Rev Neurobiol 18 71 84 17725510
  103. Maletic-Savatic M Malinow R Svoboda K 1999 Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity Science 283 1923 1927 10082466
  104. Malliri A van der Kammen RA Clark K van der Valk M Michiels F Collard JG 2002 Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours Nature 417 867 871 12075356
  105. Malmberg EK Andersson CX Gentzsch M Chen JH Mengos A Cui L Hansson GC Riordan JR 2004 Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3 J Cell Sci 117 5535 5541 15494376
  106. Manabe R Kovalenko M Webb DJ Horwitz AR 2002 GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration J Cell Sci 115 1497 1510 11896197
  107. Manser E Loo TH Koh CG Zhao ZS Chen XQ Tan L Tan I Leung T Lim L 1998 PAK kinases are directly coupled to the PIX family of nucleotide exchange factors Mol Cell 1 183 192 9659915
  108. Marie B Sweeney ST Poskanzer KE Roos J Kelly RB Davis GW 2004 Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth Neuron 43 207 219 15260957
  109. Maru Y Witte ON 1991 The BCR gene encodes a novel serine/threonine kinase activity within a single exon Cell 67 459 468 1657398
  110. McPherson CE Eipper BA Mains RE 2005 Multiple novel isoforms of Trio are expressed in the developing rat brain Gene 347 125 135 15715966
  111. McWhirter JR Galasso DL Wang JY 1993 A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins Mol Cell Biol 13 7587 7595 8246975 PMC364830
  112. Mertens AE Pegtel DM Collard JG 2006 Tiam1 takes PARt in cell polarity Trends Cell Biol 16 308 316 16650994
  113. Mertens AE Roovers RC Collard JG 2003 Regulation of Tiam1-Rac signalling FEBS Lett 546 11 16 12829230
  114. Mertens AE Rygiel TP Olivo C van der Kammen R Collard JG 2005 The Rac activator Tiam1 controls tight junction biogenesis in keratinocytes through binding to and activation of the Par polarity complex J Cell Biol 170 1029 1037 16186252 PMC2171536
  115. Miyamoto Y Yamauchi J Tanoue A Wu C Mobley WC 2006 TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology Proc Natl Acad Sci U S A 103 10444 10449 16801538 PMC1502477
  116. Moon SY Zheng Y 2003 Rho GTPase-activating proteins in cell regulation Trends Cell Biol 13 13 22 12480336
  117. Muly EC Nairn AC Greengard P Rainnie DG 2008 Subcellular distribution of the Rho-GEF Lfc in primate prefrontal cortex: effect of neuronal activation J Comp Neurol 508 927 939 18399541 PMC3789598
  118. Nadif Kasri N Nakano-Kobayashi A Malinow R Li B Van Aelst L 2009 The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors Genes Dev 23 1289 1302 19487570 PMC2701582
  119. Nakano-Kobayashi A Kasri NN Newey SE Van Aelst L 2009 The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1 Curr Biol 19 1133 1139 19481455 PMC2711225
  120. Newey SE Velamoor V Govek EE Van Aelst L 2005 Rho GTPases, dendritic structure, and mental retardation J Neurobiol 64 58 74 15884002
  121. Newsome TP Schmidt S Dietzl G Keleman K Asling B Debant A Dickson BJ 2000 Trio combines with dock to regulate Pak activity during photoreceptor axon pathfinding in Drosophila Cell 101 283 294 10847683
  122. Nishimura T Yamaguchi T Kato K Yoshizawa M Nabeshima Y Ohno S Hoshino M Kaibuchi K 2005 PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1 Nat Cell Biol 7 270 277 15723051
  123. Nishimura T Yamaguchi T Tokunaga A Hara A Hamaguchi T Kato K Iwamatsu A Okano H Kaibuchi K 2006 Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2 Mol Biol Cell 17 1273 1285 16394100 PMC1382316
  124. O’Brien SP Seipel K Medley QG Bronson R Segal R Streuli M 2000 Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos Proc Natl Acad Sci U S A 97 12074 12078 11050238 PMC17296
  125. Oh D Han S Seo J Lee JR Choi J Groffen J Kim K Cho YS Choi HS Shin H Woo J Won H Park SK Kim SY Jo J Whitcomb DJ Cho K Kim H Bae YC Heisterkamp N Choi SY Kim E 2010 Regulation of synaptic Rac1 activity, long-term potentiation maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins J Neurosci 30 14134 14144 20962234 PMC5076888
  126. Okamura K Tanaka H Yagita Y Saeki Y Taguchi A Hiraoka Y Zeng LH Colman DR Miki N 2004 Cadherin activity is required for activity-induced spine remodeling J Cell Biol 167 961 972 15569714 PMC2172468
  127. Papa M Bundman MC Greenberger V Segal M 1995 Morphological analysis of dendritic spine development in primary cultures of hippocampal neurons J Neurosci 15 1 11 7823120 PMC6578316
  128. Papadopoulos T Eulenburg V Reddy-Alla S Mansuy IM Li Y Betz H 2008 Collybistin is required for both the formation and maintenance of GABAergic postsynapses in the hippocampus Mol Cell Neurosci 39 161 169 18625319
  129. Papadopoulos T Korte M Eulenburg V Kubota H Retiounskaia M Harvey RJ Harvey K O’Sullivan GA Laube B Hulsmann S Geiger JR Betz H 2007 Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice Embo J 26 3888 3899 17690689 PMC1994120
  130. Parnas D Haghighi AP Fetter RD Kim SW Goodman CS 2001 Regulation of postsynaptic structure and protein localization by the Rho-type guanine nucleotide exchange factor dPix Neuron 32 415 424 11709153
  131. Pawson C Eaton BA Davis GW 2008 Formin-dependent synaptic growth: evidence that Dlar signals via Diaphanous to modulate synaptic actin and dynamic pioneer microtubules J Neurosci 28 11111 11123 18971454 PMC2654187
  132. Pegtel DM Ellenbroek SI Mertens AE van der Kammen RA de Rooij J Collard JG 2007 The Par-Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity Curr Biol 17 1623 1634 17825562
  133. Penzes P Cahill ME Jones KA Srivastava DP 2008 Convergent CaMK and RacGEF signals control dendritic structure and function Trends Cell Biol 18 405 413 18701290
  134. Penzes P Johnson RC Alam MR Kambampati V Mains RE Eipper BA 2000 An isoform of kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction J Biol Chem 275 6395 6403 10692441
  135. Penzes P Johnson RC Sattler R Zhang X Huganir RL Kambampati V Mains RE Eipper BA 2001 The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis Neuron 29 229 242 11182094
  136. Penzes P Jones KA 2008 Dendritic spine dynamics--a key role for kalirin-7 Trends Neurosci 31 419 427 18597863 PMC3973420
  137. Pertz O 2010 Spatio-temporal Rho GTPase signaling - where are we now? J Cell Sci 123 1841 1850 20484664
  138. Poulopoulos A Aramuni G Meyer G Soykan T Hoon M Papadopoulos T Zhang M Paarmann I Fuchs C Harvey K Jedlicka P Schwarzacher SW Betz H Harvey RJ Brose N Zhang W Varoqueaux F 2009 Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin Neuron 63 628 642 19755106
  139. Pucharcos C Fuentes JJ Casas C de la Luna S Alcantara S Arbones ML Soriano E Estivill X Pritchard M 1999 Alu-splice cloning of human Intersectin (ITSN), a putative multivalent binding protein expressed in proliferating and differentiating neurons and overexpressed in Down syndrome Eur J Hum Genet 7 704 712 10482960
  140. Radziwill G Erdmann RA Margelisch U Moelling K 2003 The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain Mol Cell Biol 23 4663 4672 12808105 PMC164848
  141. Ramakers GJ 2002 Rho proteins, mental retardation and the cellular basis of cognition Trends Neurosci 25 191 199 11998687
  142. Reddy-Alla S Schmitt B Birkenfeld J Eulenburg V Dutertre S Bohringer C Gotz M Betz H Papadopoulos T 2010 PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering Eur J Neurosci 31 1173 1184 20345913
  143. Reid T Bathoorn A Ahmadian MR Collard JG 1999 Identification and characterization of hPEM-2, a guanine nucleotide exchange factor specific for Cdc42 J Biol Chem 274 33587 33593 10559246
  144. Ren Y Li R Zheng Y Busch H 1998 Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases J Biol Chem 273 34954 34960 9857026
  145. Ridley AJ Self AJ Kasmi F Paterson HF Hall A Marshall CJ Ellis C 1993 rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo Embo J 12 5151 5160 8262058 PMC413777
  146. Rizo J Sudhof TC 1998 C2-domains, structure and function of a universal Ca2+-binding domain J Biol Chem 273 15879 15882 9632630
  147. Rodgers EE Theibert AB 2002 Functions of PI 3-kinase in development of the nervous system Int J Dev Neurosci 20 187 197 12175854
  148. Roof RW Dukes BD Chang JH Parsons SJ 2000 Phosphorylation of the p190 RhoGAP N-terminal domain by c-Src results in a loss of GTP binding activity Febs Lett 472 117 121 10781817
  149. Rose S Malabarba MG Krag C Schultz A Tsushima H Di Fiore PP Salcini AE 2007 Caenorhabditis elegans intersectin: a synaptic protein regulating neurotransmission Mol Biol Cell 18 5091 5099 17942601 PMC2096573
  150. Rosenberger G Kutsche K 2006 AlphaPIX and betaPIX and their role in focal adhesion formation European journal of cell biology 85 265 274 16337026
  151. Rossman KL Der CJ Sondek J 2005 GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors Nat Rev Mol Cell Biol 6 167 180 15688002
  152. Ryan XP Alldritt J Svenningsson P Allen PB Wu GY Nairn AC Greengard P 2005 The Rho-specific GEF Lfc interacts with neurabin and spinophilin to regulate dendritic spine morphology Neuron 47 85 100 15996550
  153. Sahay S Pannucci NL Mahon GM Rodriguez PL Megjugorac NJ Kostenko EV Ozer HL Whitehead IP 2008 The RhoGEF domain of p210 Bcr-Abl activates RhoA and is required for transformation Oncogene 27 2064 2071 17922031 PMC2676674
  154. Sahin M Greer PL Lin MZ Poucher H Eberhart J Schmidt S Wright TM Shamah SM O’Connell S Cowan CW Hu L Goldberg JL Debant A Corfas G Krull CE Greenberg ME 2005 Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse Neuron 46 191 204 15848799
  155. Saneyoshi T Wayman G Fortin D Davare M Hoshi N Nozaki N Natsume T Soderling TR 2008 Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex Neuron 57 94 107 18184567 PMC2277504
  156. Schmidt A Hall A 2002 Guanine nucleotide exchange factors for Rho GTPases: turning on the switch Genes Dev 16 1587 1609 12101119
  157. Segura I Essmann CL Weinges S Acker-Palmer A 2007 Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation Nat Neurosci 10 301 310 17310244
  158. Sfakianos MK Eisman A Gourley SL Bradley WD Scheetz AJ Settleman J Taylor JR Greer CA Williamson A Koleske AJ 2007 Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior J Neurosci 27 10982 10992 17928439 PMC6672862
  159. Shamah SM Lin MZ Goldberg JL Estrach S Sahin M Hu L Bazalakova M Neve RL Corfas G Debant A Greenberg ME 2001 EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin Cell 105 233 244 11336673
  160. Shi L Butt B Ip FC Dai Y Jiang L Yung WH Greenberg ME Fu AK Ip NY 2010 Ephexin1 is required for structural maturation and neurotransmission at the neuromuscular junction Neuron 65 204 216 20152127 PMC3718047
  161. Shin EY Shin KS Lee CS Woo KN Quan SH Soung NK Kim YG Cha CI Kim SR Park D Bokoch GM Kim EG 2002 Phosphorylation of p85 beta PIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth J Biol Chem 277 44417 44430 12226077
  162. Snyder JT Worthylake DK Rossman KL Betts L Pruitt WM Siderovski DP Der CJ Sondek J 2002 Structural basis for the selective activation of Rho GTPases by Dbl exchange factors Nat Struct Biol 9 468 475 12006984
  163. Soderling SH Langeberg LK Soderling JA Davee SM Simerly R Raber J Scott JD 2003 Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice Proc Natl Acad Sci U S A 100 1723 1728 12578964 PMC149900
  164. Sone M Hoshino M Suzuki E Kuroda S Kaibuchi K Nakagoshi H Saigo K Nabeshima Y Hama C 1997 Still life, a protein in synaptic terminals of Drosophila homologous to GDP-GTP exchangers [published erratum appears in Science 1997 Mar 7;275(5305):1405] Science 275 543 547 8999801
  165. Sone M Suzuki E Hoshino M Hou D Kuromi H Fukata M Kuroda S Kaibuchi K Nabeshima Y Hama C 2000 Synaptic development is controlled in the periactive zones of Drosophila synapses Development 127 4157 4168 10976048
  166. Steven R Kubiseski TJ Zheng H Kulkarni S Mancillas J Ruiz Morales A Hogue CW Pawson T Culotti J 1998 UNC-73 activates the Rac GTPase and is required for cell and growth cone migrations in C. elegans Cell 92 785 795 9529254
  167. Steven R Zhang L Culotti J Pawson T 2005 The UNC-73/Trio RhoGEF-2 domain is required in separate isoforms for the regulation of pharynx pumping and normal neurotransmission in C. elegans Genes Dev 19 2016 2029 16140983 PMC1199572
  168. Takeichi M 2007 The cadherin superfamily in neuronal connections and interactions Nat Rev Neurosci 8 11 20 17133224
  169. Tan EC Leung T Manser E Lim L 1993 The human active breakpoint cluster region-related gene encodes a brain protein with homology to guanine nucleotide exchange proteins and GTPase-activating proteins J Biol Chem 268 27291 27298 8262969
  170. Tang L Hung CP Schuman EM 1998 A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation Neuron 20 1165 1175 9655504
  171. Tcherkezian J Lamarche-Vane N 2007 Current knowledge of the large RhoGAP family of proteins Biol Cell 99 67 86 17222083
  172. Thomas S Ritter B Verbich D Sanson C Bourbonniere L McKinney RA McPherson PS 2009 Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons J Biol Chem 284 12410 12419 19258322 PMC2673308
  173. Togashi H Abe K Mizoguchi A Takaoka K Chisaka O Takeichi M 2002 Cadherin regulates dendritic spine morphogenesis Neuron 35 77 89 12123610
  174. Tolias KF Bikoff JB Burette A Paradis S Harrar D Tavazoie S Weinberg RJ Greenberg ME 2005 The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines Neuron 45 525 538 15721239
  175. Tolias KF Bikoff JB Kane CG Tolias CS Hu L Greenberg ME 2007 The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development Proc Natl Acad Sci U S A 104 7265 7270 17440041 PMC1855368
  176. Toni N Buchs PA Nikonenko I Bron CR Muller D 1999 LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite Nature 402 421 425 10586883
  177. Van de Ven TJ VanDongen HM VanDongen AM 2005 The nonkinase phorbol ester receptor alpha 1-chimerin binds the NMDA receptor NR2A subunit and regulates dendritic spine density J Neurosci 25 9488 9496 16221859 PMC6725706
  178. Vanderzalm PJ Pandey A Hurwitz ME Bloom L Horvitz HR Garriga G 2009 C. elegans CARMIL negatively regulates UNC-73/Trio function during neuronal development Development 136 1201 1210 19244282 PMC2685937
  179. Voncken JW van Schaick H Kaartinen V Deemer K Coates T Landing B Pattengale P Dorseuil O Bokoch GM Groffen J 1995 Increased neutrophil respiratory burst in bcr-null mutants Cell 80 719 728 7889565
  180. Wang W Bouhours M Gracheva EO Liao EH Xu K Sengar AS Xin X Roder J Boone C Richmond JE Zhen M Egan SE 2008 ITSN-1 controls vesicle recycling at the neuromuscular junction and functions in parallel with DAB-1 Traffic 9 742 754 18298590 PMC3791081
  181. Xie Z Cahill ME Penzes P 2010 Kalirin loss results in cortical morphological alterations Mol Cell Neurosci 43 81 89 19800004 PMC2818244
  182. Xie Z Photowala H Cahill ME Srivastava DP Woolfrey KM Shum CY Huganir RL Penzes P 2008 Coordination of synaptic adhesion with dendritic spine remodeling by AF-6 and kalirin-7 J Neurosci 28 6079 6091 18550750 PMC2727754
  183. Yamabhai M Hoffman NG Hardison NL McPherson PS Castagnoli L Cesareni G Kay BK 1998 Intersectin, a novel adaptor protein with two Eps15 homology and five Src homology 3 domains J Biol Chem 273 31401 31407 9813051
  184. Yamaguchi Y Pasquale EB 2004 Eph receptors in the adult brain Curr Opin Neurobiol 14 288 296 15194108
  185. Yashiro K Philpot BD 2008 Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity Neuropharmacology 55 1081 1094 18755202 PMC2590778
  186. Yuste R Majewska A 2001 On the function of dendritic spines Neuroscientist 7 387 395 11597098
  187. Zamanian JL Kelly RB 2003 Intersectin 1L guanine nucleotide exchange activity is regulated by adjacent src homology 3 domains that are also involved in endocytosis Mol Biol Cell 14 1624 1637 12686614 PMC153127
  188. Zhang H Macara IG 2006 The polarity protein PAR-3 and TIAM1 cooperate in dendritic spine morphogenesis Nat Cell Biol 8 227 237 16474385
  189. Zhang H Macara IG 2008 The PAR-6 polarity protein regulates dendritic spine morphogenesis through p190 RhoGAP and the Rho GTPase Dev Cell 14 216 226 18267090 PMC2768076
  190. Zhang H Webb DJ Asmussen H Horwitz AF 2003 Synapse formation is regulated by the signaling adaptor GIT1 J Cell Biol 161 131 142 12695502 PMC2172873
  191. Zhang H Webb DJ Asmussen H Niu S Horwitz AF 2005 A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC J Neurosci 25 3379 3388 15800193 PMC6724907
  192. Ziv NE Smith SJ 1996 Evidence for a role of dendritic filopodia in synaptogenesis and spine formation Neuron 17 91 102 8755481

Cited by

Sorted by citations

Authors
Tolias, K. F., Duman, J. G., & Um, K.
Affiliations
Baylor College of Medicine (US)
Corresponding author
Tolias, Kimberley F.
ORCID
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2011-07
Volume
94
Issue
2
Pages
133-148
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/j.pneurobio.2011.04.011
PMC
PMC3129138
OpenAlex
W2030930681
Cited by
261
References
10
Citations by year
2026: 9 · 2025: 12 · 2024: 15 · 2023: 14 · 2022: 10 · 2021: 20 · 2020: 16 · 2019: 11 · 2018: 10 · 2017: 20 · 2016: 19 · 2015: 25 · 2014: 30 · 2013: 28 · 2012: 16
FWCI
2.44
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Progress in Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (K01MH086119)
  • National Institute of Neurological Disorders and Stroke (R01NS062829)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Rho GTPases, dendritic spines, synaptic development, synaptic plasticity, guanine nucleotide exchange factor, GTPase-activating protein, actin cytoskeleton, spinogenesis, synaptogenesis, learning and memory, brain disorders
MeSH terms
Animals, Humans, Nerve Tissue Proteins, Neuromuscular Junction, Neuronal Plasticity, Neurons, Synapses, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, Protein Interaction Domains and Motifs, Neurogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review