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The Rac GTP Exchange Factor TIAM-1 Acts with CDC-42 and the Guidance Receptor UNC-40/DCC in Neuronal Protrusion and Axon Guidance


The mechanisms linking guidance receptors to cytoskeletal dynamics in the growth cone during axon extension remain mysterious. The Rho-family GTPases Rac and CDC-42 are key regulators of growth cone lamellipodia and filopodia formation, yet little is understood about how these molecules interact in growth cone outgrowth or how the activities of these molecules are regulated in distinct contexts. UNC-73/Trio is a well-characterized Rac GTP exchange factor in Caenorhabditis elegans axon pathfinding, yet UNC-73 does not control CED-10/Rac downstream of UNC-6/Netrin in attractive axon guidance. Here we show that C. elegans TIAM-1 is a Rac-specific GEF that links CDC-42 and Rac signaling in lamellipodia and filopodia formation downstream of UNC-40/DCC. We also show that TIAM-1 acts with UNC-40/DCC in axon guidance. Our results indicate that a CDC-42/TIAM-1/Rac GTPase signaling pathway drives lamellipodia and filopodia formation downstream of the UNC-40/DCC guidance receptor, a novel set of interactions between these molecules. Furthermore, we show that TIAM-1 acts with UNC-40/DCC in axon guidance, suggesting that TIAM-1 might regulate growth cone protrusion via Rac GTPases in response to UNC-40/DCC. Our results also suggest that Rac GTPase activity is controlled by different GEFs in distinct axon guidance contexts, explaining how Rac GTPases can specifically control multiple cellular functions.


Vyšlo v časopise: The Rac GTP Exchange Factor TIAM-1 Acts with CDC-42 and the Guidance Receptor UNC-40/DCC in Neuronal Protrusion and Axon Guidance. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002665
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002665

Souhrn

The mechanisms linking guidance receptors to cytoskeletal dynamics in the growth cone during axon extension remain mysterious. The Rho-family GTPases Rac and CDC-42 are key regulators of growth cone lamellipodia and filopodia formation, yet little is understood about how these molecules interact in growth cone outgrowth or how the activities of these molecules are regulated in distinct contexts. UNC-73/Trio is a well-characterized Rac GTP exchange factor in Caenorhabditis elegans axon pathfinding, yet UNC-73 does not control CED-10/Rac downstream of UNC-6/Netrin in attractive axon guidance. Here we show that C. elegans TIAM-1 is a Rac-specific GEF that links CDC-42 and Rac signaling in lamellipodia and filopodia formation downstream of UNC-40/DCC. We also show that TIAM-1 acts with UNC-40/DCC in axon guidance. Our results indicate that a CDC-42/TIAM-1/Rac GTPase signaling pathway drives lamellipodia and filopodia formation downstream of the UNC-40/DCC guidance receptor, a novel set of interactions between these molecules. Furthermore, we show that TIAM-1 acts with UNC-40/DCC in axon guidance, suggesting that TIAM-1 might regulate growth cone protrusion via Rac GTPases in response to UNC-40/DCC. Our results also suggest that Rac GTPase activity is controlled by different GEFs in distinct axon guidance contexts, explaining how Rac GTPases can specifically control multiple cellular functions.


Zdroje

1. GalloGLetourneauPC 2004 Regulation of growth cone actin filaments by guidance cues. J Neurobiol 58 92 102

2. WelchMDMullinsRD 2002 Cellular control of actin nucleation. Annu Rev Cell Dev Biol 18 247 288

3. SvitkinaTMBulanovaEAChagaOYVignjevicDMKojimaS 2003 Mechanism of filopodia initiation by reorganization of a dendritic network. J Cell Biol 160 409 421

4. KorobovaFSvitkinaT 2008 Arp2/3 complex is important for filopodia formation, growth cone motility, and neuritogenesis in neuronal cells. Mol Biol Cell 19 1561 1574

5. PakCWFlynnKCBamburgJR 2008 Actin-binding proteins take the reins in growth cones. Nat Rev Neurosci 9 136 147

6. BroseKBlandKSWangKHArnottDHenzelW 1999 Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96 795 806

7. ZallenJAYiBABargmannCI 1998 The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple aspects of axon guidance in C. elegans. Cell 92 217 227

8. KilleenMTSybingcoSS 2008 Netrin, Slit and Wnt receptors allow axons to choose the axis of migration. Dev Biol 323 143 151

9. GitaiZYuTWLundquistEATessier-LavigneMBargmannCI 2003 The netrin receptor UNC-40/DCC stimulates axon attraction and outgrowth through enabled and, in parallel, Rac and UNC-115/AbLIM. Neuron 37 53 65

10. ShekarabiMKennedyTE 2002 The netrin-1 receptor DCC promotes filopodia formation and cell spreading by activating Cdc42 and Rac1. Mol Cell Neurosci 19 1 17

11. AdlerCEFetterRDBargmannCI 2006 UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation. Nat Neurosci 9 511 518

12. AnithaANakamuraKYamadaKSudaSThanseemI 2008 Genetic analyses of roundabout (ROBO) axon guidance receptors in autism. Am J Med Genet B Neuropsychiatr Genet 147B 1019 1027

13. Hannula-JouppiKKaminen-AholaNTaipaleMEklundRNopola-HemmiJ 2005 The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia. PLoS Genet 1 e50 doi:10.1371/journal.pgen.0010050

14. BishopALHallA 2000 Rho GTPases and their effector proteins. Biochem J 348 Pt 2 241 255

15. LundquistEA 2003 Rac proteins and the control of axon development. Curr Opin Neurobiol 13 384 390

16. AzumaTWitkeWStosselTPHartwigJHKwiatkowskiDJ 1998 Gelsolin is a downstream effector of rac for fibroblast motility. Embo J 17 1362 1370

17. BiyashevaASvitkinaTKundaPBaumBBorisyG 2004 Cascade pathway of filopodia formation downstream of SCAR. J Cell Sci 117 837 848

18. NobesCDHallA 1995 Rho, rac and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamalliposia and filopodia. Cell 81 53 62

19. NorrisADDyerJOLundquistEA 2009 The Arp2/3 complex, UNC-115/abLIM, and UNC-34/Enabled regulate axon guidance and growth cone filopodia formation in Caenorhabditis elegans. Neural Dev 4 38

20. PollardTDBorisyGG 2003 Cellular motility driven by assembly and disassembly of actin filaments. Cell 112 453 465

21. AizawaHWakatsukiSIshiiAMoriyamaKSasakiY 2001 Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat Neurosci 4 367 373

22. DanCKellyABernardOMindenA 2001 Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. J Biol Chem 276 32115 32121

23. SymonsM 2000 Adhesion signaling: PAK meets Rac on solid ground. Curr Biol 10 R535 537

24. ShakirMAJiangKStruckhoffECDemarcoRSPatelFB 2008 The Arp2/3 Activators WAVE and WASP Have Distinct Genetic Interactions With Rac GTPases in Caenorhabditis elegans Axon Guidance. Genetics 179 1957 1971

25. DemarcoRSLundquistEA 2010 RACK-1 acts with Rac GTPase signaling and UNC-115/abLIM in Caenorhabditis elegans axon pathfinding and cell migration. PLoS Genet 6 e1001215 doi:10.1371/journal.pgen.1001215

26. HallA 1992 Ras-related GTPases and the cytoskeleton. Molecular biology of the cell 3 475 479

27. KubiseskiTJCulottiJPawsonT 2003 Functional analysis of the Caenorhabditis elegans UNC-73B PH domain demonstrates a role in activation of the Rac GTPase in vitro and axon guidance in vivo. Mol Cell Biol 23 6823 6835

28. LundquistEAReddienPWHartwiegEHorvitzHRBargmannCI 2001 Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. Development 128 4475 4488

29. WuYCChengTWLeeMCWengNY 2002 Distinct rac activation pathways control Caenorhabditis elegans cell migration and axon outgrowth. Dev Biol 250 145 155

30. StevenRKubiseskiTJZhengHKulkarniSMancillasJ 1998 UNC-73 activates the Rac GTPase and is required for cell and growth cone migrations in C. elegans. Cell 92 785 795

31. HabetsGGScholtesEHZuydgeestDvan der KammenRAStamJC 1994 Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77 537 549

32. SoneMHoshinoMSuzukiEKurodaSKaibuchiK 1997 Still life, a protein in synaptic terminals of Drosophila homologous to GDP-GTP exchangers. Science 275 543 547

33. MatsuoNHoshinoMYoshizawaMNabeshimaY 2002 Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth. J Biol Chem 277 2860 2868

34. MatsuoNTeraoMNabeshimaYHoshinoM 2003 Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology. Mol Cell Neurosci 24 69 81

35. HoshinoMSoneMFukataMKurodaSKaibuchiK 1999 Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1. J Biol Chem 274 17837 17844

36. Marchler-BauerALuSAndersonJBChitsazFDerbyshireMK CDD: a Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res 39 D225 229

37. AltschulSFGishWMillerWMyersEWLipmanDJ 1990 Basic local alignment search tool. J Mol Biol 215 403 410

38. BaumeisterMAMartinuLRossmanKLSondekJLemmonMA 2003 Loss of phosphatidylinositol 3-phosphate binding by the C-terminal Tiam-1 pleckstrin homology domain prevents in vivo Rac1 activation without affecting membrane targeting. J Biol Chem 278 11457 11464

39. MichielsFStamJCHordijkPLvan der KammenRARuuls-Van StalleL 1997 Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation. J Cell Biol 137 387 398

40. WorthylakeDKRossmanKLSondekJ 2000 Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Nature 408 682 688

41. StruckhoffECLundquistEA 2003 The actin-binding protein UNC-115 is an effector of Rac signaling during axon pathfinding in C. elegans. Development 130 693 704

42. NewsomeTPSchmidtSDietzlGKelemanKAslingB 2000 Trio combines with dock to regulate Pak activity during photoreceptor axon pathfinding in Drosophila. Cell 101 283 294

43. LeeuwenFNKainHEKammenRAMichielsFKranenburgOW 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

44. YangYLundquistEA 2005 The actin-binding protein UNC-115/abLIM controls formation of lamellipodia and filopodia and neuronal morphogenesis in Caenorhabditis elegans. Mol Cell Biol 25 5158 5170

45. ZipkinIDKindtRMKenyonCJ 1997 Role of a new Rho family member in cell migration and axon guidance in C. elegans. Cell 90 883 894

46. NishimuraTYamaguchiTKatoKYoshizawaMNabeshimaY 2005 PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7 270 277

47. Montenegro-VenegasCTortosaERossoSPerettiDBollatiF MAP1B regulates axonal development by modulating Rho-GTPase Rac1 activity. Mol Biol Cell 21 3518 3528

48. ReddienPWHorvitzHR 2000 CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol 2 131 136

49. HedgecockEMCulottiJGHallDH 1990 The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4 61 85

50. HaoJCYuTWFujisawaKCulottiJGGengyo-AndoK 2001 C. elegans slit acts in midline, dorsal-ventral, and anterior-posterior guidance via the SAX-3/Robo receptor. Neuron 32 25 38

51. FlanaganJGVanderhaeghenP 1998 The ephrins and Eph receptors in neural development. Annu Rev Neurosci 21 309 345

52. GeorgeSESimokatKHardinJChisholmAD 1998 The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans. Cell 92 633 643

53. ZallenJAKirchSABargmannCI 1999 Genes required for axon pathfinding and extension in the C. elegans nerve ring. Development 126 3679 3692

54. HaoJCAdlerCEMebaneLGertlerFBBargmannCI 2010 The tripartite motif protein MADD-2 functions with the receptor UNC-40 (DCC) in Netrin-mediated axon attraction and branching. Dev Cell 18 950 960

55. Watari-GoshimaNOguraKWolfFWGoshimaYGarrigaG 2007 C. elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations. Nat Neurosci 10 169 176

56. ForsthoefelDJLieblECKolodziejPASeegerMA 2005 The Abelson tyrosine kinase, the Trio GEF and Enabled interact with the Netrin receptor Frazzled in Drosophila. Development 132 1983 1994

57. Briancon-MarjolletAGhoghaANawabiHTrikiIAuziolC 2008 Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Mol Cell Biol 28 2314 2323

58. IshiiNWadsworthWGSternBDCulottiJGHedgecockEM 1992 UNC-6, a laminin-related protein, guides cell and pioneer axon migrations in C. elegans. Neuron 9 873 881

59. YuTWHaoJCLimWTessier-LavigneMBargmannCI 2002 Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function. Nat Neurosci 5 1147 1154

60. KnobelKMJorgensenEMBastianiMJ 1999 Growth cones stall and collapse during axon outgrowth in Caenorhabditis elegans. Development 126 4489 4498

61. NorrisADLundquistEA 2011 UNC-6/netrin and its receptors UNC-5 and UNC-40/DCC modulate growth cone protrusion in vivo in C. elegans. Development 138 4433 4442

62. Levy-StrumpfNCulottiJG 2007 VAB-8, UNC-73 and MIG-2 regulate axon polarity and cell migration functions of UNC-40 in C. elegans. Nat Neurosci 10 161 168

63. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94

64. MelloCCKramerJMStinchcombDAmbrosV 1991 Efficient gene transfer in C. elegans: extrachromosomal maintenance and intregration of transforming sequences. EMBO J 10 3959 3970

65. KamathRSFraserAGDongYPoulinGDurbinR 2003 Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421 231 237

66. ColletJSpikeCALundquistEAShawJEHermanRK 1998 Analysis of osm-6, a gene that affects sensory cilium structure and sensory neuron function in Caenorhabditis elegans. Genetics 148 187 200

67. JinYJorgensenEHartwiegEHorvitzHR 1999 The Caenorhabditis elegans gene unc-25 encodes glutamic acid decarboxylase and is required for synaptic transmission but not synaptic development. J Neurosci 19 539 548

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