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TGF-ßS and Their Roles in the Regulation of Neuron Survival

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Molecular and Cellular Biology of Neuroprotection in the CNS

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 513))

Abstract

Transforming growth factor-ßs (TGF-ßs) are a still growing superfamily of cytokines with widespread distribution and diverse biological functions. They fall into several subfamilies including the TGF-ßs 1, 2, and 3, the bone morphogenetic proteins (BMPs), the growth/differentiation factors (GDFs), activins and inhibins, and the members of the glial cell line-derived neurotrophic factor family. Following a brief description of their general roles and signaling in development, maintenance of homeostasis, and disease, we shall focus on their distribution in the CNS and their involvement in regulating neuron survival and death.

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References

  1. Roberts AB, Sporn MB. The transforming growth factor-ßs. In: Sporn MB, Roberts AB, Eds. Handbook of Experimental Pharmacology. Heidelberg: Springer Verlag, 1990;95:419–472.

    Google Scholar 

  2. Wahl SM. Transforming growth factor beta (TGF-ß) in inflammation: A cause and a cure. J Clin Immunol 1992; 12:66–74.

    Article  Google Scholar 

  3. Kingsley DM. The TGF-J3 superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes Dev 1994; 8:133–146.

    Article  PubMed  CAS  Google Scholar 

  4. Flanders KC, L decke G, Engels S, Cissel DS, Roberts AB, Kondaiah P et al. Localization and actions of transforming growth factor-(3s in the embryonic nervous system. Development 1991; 113:183–191.

    PubMed  CAS  Google Scholar 

  5. Finch CE, Laping NJ, Morgan TE, Nicholson NR, Pasinetti GM. TGF-131 is an organizer of responses to neurodegeneration. J Cell Biochem 1993; 53:314–322.

    Article  PubMed  CAS  Google Scholar 

  6. Krieglstein K, Rufer M, Suter-Crazzolara C, Unsicker K. Neural functions of the transforming growth factors ß. Int J Dev Neurosci 1995; 13:301–315.

    Article  PubMed  CAS  Google Scholar 

  7. Moses HL, Branum EL, Proper JA, Robinson RA. Transforming growth factor production by chemically transformed cells. Cancer Res 1981; 41:2842–2848.

    PubMed  CAS  Google Scholar 

  8. Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci USA 1981; 78:5339–5343.

    Article  PubMed  CAS  Google Scholar 

  9. McDonald NQ, Hendrickson WA. A structural superfamily of growth factors containing a cystine knot motif. Cell 1993; 73:421–424.

    Article  PubMed  CAS  Google Scholar 

  10. Krieglstein K, Henheik P, Farkas L, Jaszai J, Gaiter D, Krohn K et al. GDNF requires TGF13 for establishing its neurotrophic activity. J Neurosci 1998; 18:9822–9834.

    PubMed  CAS  Google Scholar 

  11. Schober A, Hertel R, Arumae U, Farkas L, Jaszai J, Krieglstein K et al. Glial cell line-derived neurotrophic factor rescues target-deprived sympathetic spinal cord neurons but requires transforming growth factor-beta as cofactor in vivo. J Neurosci 1999; 19:2008–2015.

    PubMed  CAS  Google Scholar 

  12. Flanders KC, Fen RF, Lippa CF. Transforming growth factor-13s in neurodegenerative disease. Prog Neurobiol 1998; 54:71–85.

    Article  PubMed  CAS  Google Scholar 

  13. Lawrence DA. Transforming growth factor-beta: A general review. Eur Cytokine Netw 1996; 7:363–374.

    PubMed  CAS  Google Scholar 

  14. Mehler MF, Mabie PC, Zhang D, Kessler JA. Bone morphogenetic proteins in the nervous system. Trends Neurosci 1997; 20:309–317.

    Article  PubMed  CAS  Google Scholar 

  15. Ebendal T, Bengtsson H, S derstr m S. Bone morphogenetic proteins and their receptors: Potential functions in the brain. J Neurosci Res 1998; 51:139–146.

    Article  PubMed  CAS  Google Scholar 

  16. Unsicker K, Suter-Crazzolara C, Krieglstein K. Neurotrophic roles of GDNF and related factors. In: Hefti F, ed. Handbook of Experimental Pharmacology. Heidelberg: Springer Verlag, 1999; 134:189–224.

    Google Scholar 

  17. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753–791.

    Article  PubMed  CAS  Google Scholar 

  18. Kiefer R, Streit WJ, Toykka KV, Kreutzberg GW, Hartung HP. Transforming growth factor-beta 1: A lesion-associated cytokine of the nervous system. Int J Dev Neurosci 1995; 13:331–339.

    Article  PubMed  CAS  Google Scholar 

  19. Pratt BM, McPherson JM. TGF-(3 in the central nervous system: Potential roles in ischemic injury and neurodegenerative diseases. Cytokine Growth Factor Rev 1997; 8:267–292.

    Article  PubMed  CAS  Google Scholar 

  20. Raivich G, Jones JJ, Werner A, Bluthmann H, Doetschman T, Kreutzberg GW. Molecular signals for glial activation: pro-and anti-inflammatory cytokines in the injured brain. Acta Neurochir Suppl 1999; 73,21–30.

    PubMed  CAS  Google Scholar 

  21. Ohta M, Greenberger JS, Anklesaria P, Bassols A, Massague J. Two forms of transforming growth factor-beta distinguished by multipotential haematopoietic progenitor cells. Nature 1987; 329:539–541.

    Article  PubMed  CAS  Google Scholar 

  22. Madisen L, Webb NR, Rose TM, Marquardt H, Ikeda T, Twardzik D et al. Transforming growth factor-beta 2: eDNA cloning and sequence analysis. DNA 1988; 7:1–8.

    Article  PubMed  CAS  Google Scholar 

  23. Derynek R, Lindquist PB, Lee A, Wen D, Tamm J, Graycar JL et al. A new type of transforming growth factor-beta, TGF-beta 3. EMBO J 1988; 7:3737–3743.

    Google Scholar 

  24. Burt DW, Paton IR. Evolutionary origins of the transforming growth factor-beta gene family. DNA Cell Biol 1992;11:497–510.

    Article  PubMed  CAS  Google Scholar 

  25. Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994; 5:99–118.

    Article  PubMed  CAS  Google Scholar 

  26. Nathan C, Sporn M. Cytokines in context. J Cell Biol 1991;113:981–986.

    Article  PubMed  CAS  Google Scholar 

  27. Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A, Woo W et al. Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid. Nature 1986; 321:776–779.

    Article  PubMed  CAS  Google Scholar 

  28. Ling N, Ying SY, Ueno N, Esch F, Denoroy L, Guillemin R. Isolation and partial characterization of a Mr 32,000 protein with inhibin activity from porcine follicular fluid. Proc Natl Acad Sci USA 1985; 82:7217–7221.

    Article  PubMed  CAS  Google Scholar 

  29. Petraglia F, Vaughan J, Vale W. Inhibin and activin modulate the release of gonadotropinreleasing hormone, human chorionic gonadotropin, and progesterone from cultured human placenta cells. Proc Natl Acad Sci USA 1989; 86:5114–5117.

    Article  PubMed  CAS  Google Scholar 

  30. Eto Y, Tsuji T, Takezawa M, Takano S, Yokogawa X, Shibai H. Purification and characterization of erythroid differentiation factor (EDF) isolated from human leukemia cell line THP-1. Biochem Biophys Res Commun 1987; 142:1095–1103.

    Article  PubMed  CAS  Google Scholar 

  31. Smith JC, Price BM, Van Nimmen K, Huylebroeck D. Identification of a potent Xenopus mesodem-inducing factor as a homologue of activin A. Nature 1990; 345:729–731.

    Article  PubMed  CAS  Google Scholar 

  32. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whiners MJ, Kriz RW et al. Novel regulators of bone formation: molecular clones and activities. Science 1988; 242:1528–1534.

    Article  PubMed  CAS  Google Scholar 

  33. Hogan BL. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 1996; 10:1580–1594.

    Article  PubMed  CAS  Google Scholar 

  34. Ferguson EL, Anderson KV. Decapentaplegic acts as a morphogen to organize dorsal-ventral pattern in the Drosophila embryo. Cell 1992; 71:451–461.

    Article  PubMed  CAS  Google Scholar 

  35. Weeks DL, Melton DA. A maternal mRNA localized to the vegetal hemisphere in Xenopus eggs codes for a growth factor related to TGF-beta. Cell 1987; 51:861–867.

    Article  PubMed  CAS  Google Scholar 

  36. Thomsen GH, Melton DA. Processed Vgl protein is an axial mesoderm inducer in Xenopus. Cell 1993; 74:433–441.

    Article  PubMed  CAS  Google Scholar 

  37. Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR. Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. Nature 1993; 361:543–547.

    Article  PubMed  CAS  Google Scholar 

  38. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993; 260:1130–1132.

    Article  PubMed  CAS  Google Scholar 

  39. Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson EM Jr. et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 1996; 384:467–470.

    Article  PubMed  CAS  Google Scholar 

  40. Milbrandt J, de Sauvage FJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG et al. Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 1998; 20:1–20.

    Article  Google Scholar 

  41. Baloh RH, Tansey MG, Lampe PA, Fahrner TJ, Enomoto H, Simburger KS et al. Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron 1998; 21:1291–1302.

    Article  PubMed  CAS  Google Scholar 

  42. Rosenblad C, Gronborg M, Hansen C, Blom N, Meyer M, Johansen J et al. In vivo protection of nigral dopamine neurons by lentiviral gene transfer of the novel GDNF-family member neublastin/artemin. Mol Cell Neurosci 2000; 15:199–214.

    Article  PubMed  CAS  Google Scholar 

  43. Treanor JJ, Goodman L, de Sauvage F, Stone DM, Poulsen KT, Beck CD et al. Characterization of a multicomponent receptor for GDNF. Nature 1996; 382:80–83.

    Article  PubMed  CAS  Google Scholar 

  44. Blanchard MG, Josso N. Source of the anti-Mullerian hormone synthesized by the fetal testis: Mullerian-inhibiting activity of fetal bovine Sertoli cells in tissue culture. Pediatr Res 1974; 8:968–971.

    Article  PubMed  CAS  Google Scholar 

  45. Colavita A, Krishna S, Zheng H, Padgett RW, Culotti JG. Pioneer axon guidance by UNC129, a C. elegans TGF-beta. Science 1998; 281:706–709.

    Article  PubMed  CAS  Google Scholar 

  46. Ren P, Lim CS, Johnsen R, Albert PS, Pilgrim D, Riddle DL. Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 1996; 274:1389–1391.

    Article  PubMed  CAS  Google Scholar 

  47. Daopin S, Piez KA, Ogawa Y, Davies DR. Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily. Science 1992; 257:369–373.

    Article  PubMed  CAS  Google Scholar 

  48. Schlunegger MP, Gr tter MG. An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-(32. Nature 1992; 358:430–434.

    Article  PubMed  CAS  Google Scholar 

  49. Griffith DL, Keck PC, Sampath TK, Rueger DC, Carlson WD. Three-dimensional structure of recombinant human osteogenic protein 1: Structural paradigm for the transforming growth factor 3 superfamily. Proc Natl Acad Sci USA 1996;93:878–883.

    Article  PubMed  CAS  Google Scholar 

  50. Archer SJ, Bax A, Roberts AB, Sporn MB, Ogawa Y, Piez KA et al. Transforming growth factor beta 1: Secondary structure as determined by heteronuclear magnetic resonance spectroscopy. Biochemistry 1993; 32:1164–1171.

    Article  PubMed  CAS  Google Scholar 

  51. Hinck AP, Archer SJ, Qian SW, Roberts AB, Sporn MB, Weatherbee JA et al. Transforming growth factor beta 1: Three-dimensional structure in solution and comparison with the X-ray structure of transforming growth factor beta 2. Biochemistry 1996; 35:8517–8534.

    Article  PubMed  CAS  Google Scholar 

  52. Sun PD, Davis DR. The cystine-knot growth-factor superfamily. Annu Rev Biophys Biomol Struct 1995; 24:269–291.

    Article  PubMed  CAS  Google Scholar 

  53. Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990; 6:597–641.

    Article  PubMed  CAS  Google Scholar 

  54. Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J et al. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 1992; 267:19027–19030.

    PubMed  CAS  Google Scholar 

  55. Lopez-Casillas F, Wrana JL, Massague J. Betaglycan presents ligand to the TGF beta signaling receptor. Cell 1993; 73:1435–1444.

    Article  PubMed  CAS  Google Scholar 

  56. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M et al. TGF beta signals through a heteromeric protein kinase receptor complex. Cell 1992;71:1003–1014.

    Article  PubMed  CAS  Google Scholar 

  57. Liu F, Ventura F, Doody J, Massague J. Human type II receptor for bone morphogenic proteins (BMPs): Extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 1995; 15:3479–3486.

    PubMed  CAS  Google Scholar 

  58. Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P et al. Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 1995; 92:7632–7636.

    Article  PubMed  CAS  Google Scholar 

  59. Yamashita H, ten Dijke P, Franzen P, Miyazono K, Heldin CH. Formation of heterooligomeric complexes of type I and type II receptors for transforming growth factor-beta. J Biol Chem 1994; 269:20172–20178.

    PubMed  CAS  Google Scholar 

  60. Attisano L, Wrana JL, Montalvo E, Massague J Activation of signalling by the activin receptor complex. Mol Cell Biol 1996; 16:1066–1073.

    PubMed  CAS  Google Scholar 

  61. Willis SA, Zimmerman CM, Li LI, Mathews LS. Formation and activation by phosphorylation of activin receptor complexes. Mol Endocrinol 1996; 10:367–379.

    Article  PubMed  CAS  Google Scholar 

  62. Franzen P, Heldin CH, Miyazono K. The GS domain of the transforming growth factor-beta type I receptor is important in signal transduction. Biochem Biophys Res Commun 1995; 207:682–689.

    Article  PubMed  CAS  Google Scholar 

  63. Wieser R, Wrana JL, Massague J. GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J 1995; 14:2199–2208.

    PubMed  CAS  Google Scholar 

  64. Durbec P, Marcos-Gutierrez CV, Kilkenny C, Grigoriou M, Wartiowaara K, Suvanto P et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature 1996; 381:789–793.

    Article  PubMed  CAS  Google Scholar 

  65. Trupp M, Arenas E, Fainzilber M, Nilsson AS, Sieber BA, Grigoriou M et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 1996; 381:785–789.

    Article  PubMed  CAS  Google Scholar 

  66. Thompson J, Doxakis E, Pinon LG, Strachan P, Buj-Bello A, Wyatt S et al. GFRalpha-4, a new GDNF family receptor. Mol Cell Neurosci 1998; 11:117–126.

    Article  PubMed  CAS  Google Scholar 

  67. Jing S, Yu Y, Fang M, Hu Z, Holst PL, Boone T et al. GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem 1997; 272:33111–33117.

    Article  PubMed  CAS  Google Scholar 

  68. Raftery LA, Twombly V, Wharton K, Gelbart WM. Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics 1995; 139:241–254.

    PubMed  CAS  Google Scholar 

  69. Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 1995; 139:1347–1358.

    PubMed  CAS  Google Scholar 

  70. Savage C, Das P, Finelli AL, Townsend SR, Sun CY, Baird SE et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components. Proc Natl Acad Sci USA 1996; 93:790–794.

    Article  PubMed  CAS  Google Scholar 

  71. Hoodless PA, Haerry T, Abdollah S, Stapleton M, O Connor MB, Attisano L et al. MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 1996; 85:489–500.

    Article  PubMed  CAS  Google Scholar 

  72. Liu F, Hata A, Baker JC, Doody J, Carcamo J, Harland RM, Massague J. A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 1996; 381:620–623.

    Article  PubMed  CAS  Google Scholar 

  73. Chen Y, Lebrun JJ, Vale W. Regulation of transforming growth factor beta-and activininduced transcription by mammalian Mad proteins. Proc Nat! Acad Sci USA 1996; 93:12992–12997.

    Article  CAS  Google Scholar 

  74. Lagna G, Hata A, Hemmati-Brivanlou A, Massague J. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature 1996; 383:832–836.

    Article  PubMed  CAS  Google Scholar 

  75. Zhang Y, Feng X, We R, Derynck R. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 1996; 383:168–172.

    Article  PubMed  CAS  Google Scholar 

  76. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E et al. DPC4, a candidate tumor suppressor gene at human chromosome 18g21.1. Science 1996; 271:350–353.

    Article  PubMed  CAS  Google Scholar 

  77. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390:465–471.

    Article  PubMed  CAS  Google Scholar 

  78. Hill CS. The Smads. Int J Biochem Cell Biol 1999; 31:1249–1254.

    Article  PubMed  CAS  Google Scholar 

  79. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997; 389:631–635.

    Article  PubMed  CAS  Google Scholar 

  80. Imamura T, Takase M, Nishihara A, Oeda E, Hanai J, Kawabata M et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 1997; 389:622–626.

    Article  PubMed  CAS  Google Scholar 

  81. Itoh S, Landstrom M, Hermansson A, Itoh F, Heldin CH, Heldin NE et al. Transforming growth factor betal induces nuclear export of inhibitory Smad7. J Biol Chem 1998; 273:29195–29201.

    Article  PubMed  CAS  Google Scholar 

  82. Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 1998; 95:779–791.

    Article  PubMed  CAS  Google Scholar 

  83. Macias-Silva M, Abdollah S, Hoodless PA, Pirone R, Attisano L, Wrana JL. MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 1996; 87:1215–1224.

    Article  PubMed  CAS  Google Scholar 

  84. Kretzschmar M, Liu F, Hata A, Doody J, Massague J. The TGF-beta family mediator Smadl is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 1997; 11:984–995.

    Article  PubMed  CAS  Google Scholar 

  85. Kretzschmar M, Massague J. Smads: mediators and regulators of TGF-beta signaling. Curr Opin Genet Dev 1998; 8:103–111.

    Article  PubMed  CAS  Google Scholar 

  86. Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 1997; 389:85–89.

    Article  PubMed  CAS  Google Scholar 

  87. Feng XH, Zhang Y, Wu RY, Derynck R. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-beta-induced transcriptional activation. Genes Dev 1998; 12:2153–2163.

    Article  PubMed  CAS  Google Scholar 

  88. Wotton D, Lo RS, Lee S, Massague J. A Smad transcriptional corepressor. Cell 1999; 97:29–39.

    Article  PubMed  CAS  Google Scholar 

  89. Lo RS, Massague J. Ubiquitin-dependent degradation of TGF-beta-activated Smad2. Nat Cell Biol 1999; 1:472–478.

    Article  PubMed  CAS  Google Scholar 

  90. Unsicker K, Flanders KC, Cissel DS, Lafyatis R, Sporn MB. Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience 1991; 44:613–625.

    Article  PubMed  CAS  Google Scholar 

  91. Pelton RW, Saxena B, Jones M, Moses HL, Gold LI. Immunhistochemical localization of TGF-(31, TGF-02 and TGF(33 in mouse embryo: Expression patterns suggest multiple roles during embryonic development. J Cell Biol 1991; 115:1091–1105.

    Article  PubMed  CAS  Google Scholar 

  92. Pelton RW, Dickinson ME, Moses HL, Hogan BLM. In-situ hybridization analysis of TGF03 RNA expression during mouse development: comparative studies with TGF-ßl and 132. Development 1991; 110:609–620.

    Google Scholar 

  93. B ttner M, Unsicker K, Suter-Crazzolara C. Expression of TGF- ß type II receptor mRNA in the CNS. NeuroReport 1996; 7:2903–2907.

    Article  Google Scholar 

  94. Gaiter D, Bottner M, Unsicker K. Developmental regulation of the serotonergic transmitter phenotype in rostral and caudal raphe neurons by transforming growthfactor-betas. J Neurosci Res 1999; 56:531–538.

    Article  Google Scholar 

  95. Unsicker K, Meier C, Krieglstein K, Sailor BM, Flanders KC. Expression, localization, and function of transforming growth factor-ßs in embryonic chick spinal cord, hindbrain, and dorsal root ganglia. J Neurobiol 1996; 29:262–276.

    Article  PubMed  CAS  Google Scholar 

  96. Constam DB, Schmid P, Aguzzi A, Schachner M, Fontana A. Transient production of TGF(32 by postnatal cerebellar neurons and its effect on neuroblast proliferation. Eur J Neurosci 1994; 6:766–778.

    Article  PubMed  CAS  Google Scholar 

  97. Peress NS, Perillo E. Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer s disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. J Neuropathol Exp Neurol 1995; 54:802–811.

    Article  PubMed  CAS  Google Scholar 

  98. Flanders KC, Lippa CF, Smith TW, Pollen DA, Sporn MB. Altered expression of transforming growth factor-beta in Alzheimer s disease. Neurology. 1995; 45:1561–1569.

    Article  PubMed  CAS  Google Scholar 

  99. Unsicker K. The chromaffin cell: paradigm in cell development and growth factor biology. J Anat 1993; 183:207–221.

    PubMed  CAS  Google Scholar 

  100. Unsicker K, Krieglstein K. Growth factors in chromaffin cells. Prog Neurobiol 1996; 48:307–324.

    Article  PubMed  CAS  Google Scholar 

  101. Bttner M, Krieglstein K, Unsicker K. The transforming growth factor-betas: Structure, signaling, and roles in nervous system development and functions. J Neurochem 2000; 75:2227–2240.

    Article  Google Scholar 

  102. Wolf N, Krohn K, Sieger S, Frodin M, Gammeltoft S, Krieglstein K et al. Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro. Neuroscience 1999; 90:629–41.

    Article  PubMed  CAS  Google Scholar 

  103. Finotto S, Krieglstein K, Schober A, Deimling F, Lindner K, Bruhl B et al. Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells. Development 1999; 126:2935–2944.

    PubMed  CAS  Google Scholar 

  104. Combs SE, Krieglstein K, Unsicker K. Reduction of endogenous TGF-beta increases proliferation of developing adrenal chromaffin cells in vivo. J Neurosci Res 2000; 59:379–383.

    Article  PubMed  CAS  Google Scholar 

  105. Combs SE, Krieglstein K, Ernsberger U, Unsicker K. Immuno-neutralization of endogenous TGF-ß does not affect phenotypid development of sympathoadrenal progenitors into adrenal chromaffin cells. Mech Dev 2001; 109:295–302.

    Article  PubMed  CAS  Google Scholar 

  106. Martinou JC, le van Thai A, Valette A, Weber MJ Transforming growth factor ßi is a potent survival factor for rat embryo motoneurons in culture. Dev Brain Res 1990; 52:175–181.

    Article  CAS  Google Scholar 

  107. Chalazonitis A, Kalberg J, Twardzik DR, Morrison RS, Kessler JA. Transforming growth factor beta has neurotrophic actions on sensory neurons in vitro and is synergistic with nerve growth factor. Dev Biol 1992; 152:121–132.

    Article  PubMed  CAS  Google Scholar 

  108. Krieglstein K, Unsicker K. Transforming growth factor-ß promotes survival of midrain dopaminergic neurons and protects them against N-methyl-4-phenylpyridinium ion toxicity. Neuroscience 1994; 63:1189–1196.

    Article  PubMed  CAS  Google Scholar 

  109. Krieglstein K, Suter-Crazzolara C, Fischer WH, Unsicker K. TGF-j3 superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J 1995; 14:736–742.

    PubMed  CAS  Google Scholar 

  110. Poulsen KT, Armanini MP, Klein RD, Hynes MA, Phillips HS, Rosenthal A. TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons. Neuron 1994; 13:1245–1252.

    Article  PubMed  CAS  Google Scholar 

  111. Gaiter D, Unsicker K. Regulation of the transmitter phenotype of rostra’ and caudal groups of cultured serotonergic raphe neurons. Neuroscience 1999; 88:549–559.

    Article  Google Scholar 

  112. Krieglstein K, Unsicker K. Distinct modulatory actions of TGF-ß and LIF on neurotrophinmediated survival of developing sensory neurons. Neurochem Res 1996; 21:849–856.

    Article  Google Scholar 

  113. Krieglstein K, Farkas L, Unsicker K. TGF-beta regulates the survival of ciliary ganglionic neurons synergistically with ciliary neurotrophic factor and neurotrophins. J Neurobiol 1998; 37:563–572.

    Article  PubMed  CAS  Google Scholar 

  114. Gouin A, Bloch-Gallego E, Tanaka H, Rosenthal A, Henderson CE. Transforming growth factor-beta 3, glial cell line-derived neurotrophic factor, and fibroblast growth factor-2, act in different manners to promote motoneuron survival in vitro. J Neurosci Res 1996; 43:454–464.

    Article  PubMed  CAS  Google Scholar 

  115. Ishihara A, Saito H, Abe K. Transforming growth factor-beta 1 and -beta 2 promote neurite sprouting and elongation of cultured rat hippocampal neurons. Brain Res 1994; 639:21–25

    Article  PubMed  CAS  Google Scholar 

  116. Abe K, Chu PJ, Ishihara A, Saito H. Transforming growth factor-beta 1 promotes re-elongation of injured axons of cultured rat hippocampal neurons. Brain Res 1996; 723:206–209.

    Article  PubMed  CAS  Google Scholar 

  117. Cameron JS, Lhuillier L, Subramony P, Dryer SE. Developmental regulation of neuronal K+ channels by target-derived TGF beta in vivo and in vitro. Neuron 1998; 21:1045–1053.

    Article  PubMed  CAS  Google Scholar 

  118. Cameron JS, Dryer L, Dryer SE. Regulation of neuronal K(+) currents by target-derived factors: opposing actions of two different isoforms of TGFbeta. Development 1999; 126:4157–4164

    PubMed  CAS  Google Scholar 

  119. Zhang F, Endo S, Cleary LJ, Eskin A, Byrne 1H. Role of transforming growth factor-beta in long-term synaptic facilitation in Aplysia. Science 1997; 275:1318–1320.

    Article  PubMed  CAS  Google Scholar 

  120. Toepfer M, Fischer P, Abicht A, Lochmuller H, Pongratz D, Muller-Felber W. Localization of transforming growth factor beta in association with neuromuscular junctions in adult human muscle. Cell Mol Neurobiol 1999; 19:297–300.

    PubMed  CAS  Google Scholar 

  121. McLennan IS, Koishi K, Zhang M, Murakami N. The non-synaptic expression of transforming growth factor-beta 2 is neurally regulated and varies between skeletal muscle fibre types. Neuroscience 1998; 87:845–853.

    Article  PubMed  CAS  Google Scholar 

  122. Ren RF, Flanders KC. Transforming growth factors-beta protect primary rat hippocampal neuronal cultures from degradation induced by beta-amyloid peptide. Brain Res 1996; 732:16–24.

    Article  PubMed  CAS  Google Scholar 

  123. Ren RF, Hawver DB, Kim RS, Flanders KC. Transforming growth factor beta protects human hNT cells from degradation induced by beta-amyloid peptide:involvement of the TGF-beta type II receptor. Mol Brain Res 1997; 48:315–322.

    Article  PubMed  CAS  Google Scholar 

  124. Prehn JH, Bindokas VP, Jordan J, Galindo MF, Ghadge GD, Roos RP et al. Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons. Mol Pharmacol 1996; 49:319–328.

    PubMed  CAS  Google Scholar 

  125. Prehn JHM, Miller RJ. Opposite effects of TGF-ßl on rapidly-and slowly-triggered excitotoxic injury. Neuropharmacology 1996; 35:249–256.

    Article  PubMed  CAS  Google Scholar 

  126. Prehn JHM, Bindokas VP, Marcuccilli CJ, Krajewski S, Reed JC, Miller RJ. Regulation of Bc12 protein expression and calicum homeostasis by transforming growth factor ß confers wide-ranging protection of hippocampal neurons. Proc natl Acad Sci USA 1994; 91:12599–12603.

    Article  PubMed  CAS  Google Scholar 

  127. Meucci O, Miller RJ. pg120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action by TGF-betal. J Neurosci 1996; 16:4080–4088.

    PubMed  CAS  Google Scholar 

  128. Chao CC, Hu S, Tsang M, Weatherbee JM, Molitor TW, Anderson WR et al. Effects of transforming growth factor-3 on murine astrocyte glutamine synthase activity. J Clin Invest 1992; 90:1786–1793.

    Article  PubMed  CAS  Google Scholar 

  129. Kane CJM, Brown GJ, Phelan KD. Transforming growth factor-132 increases NMDA recepptor-mediated excitotoxicity in rat cerebral cortical neurons independently of glia. Neurosci Lett 1996; 204:93–96.

    Article  PubMed  CAS  Google Scholar 

  130. Blottner D, Wolf N, Lachmund A, Flanders KC, Unsicker K. TGF-0 rescues target-derived preganglionic sympathetic iieurons in the spinal cord. Eur J Neurosci 1996; 8:202–210.

    Article  PubMed  CAS  Google Scholar 

  131. Schober A, Unsicker K. Growth and neurotrophic factors regulating development and maintenance of sympathetic preganglionic neurons. Intl Rev Cytology 2001; 205:37–76

    Article  CAS  Google Scholar 

  132. Sauer H, Rosenblad C, Bj rklund. A. Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc natl Acad Sci USA 1995; 92:8935–8939.

    Article  PubMed  CAS  Google Scholar 

  133. Logan A, Berry M, Gonzalez AM, Frautschy SA, Sporn MB, Baird A. Effects of transforming growth factor 31 on scar production in the injured central nervous system of the rat. Eur J Neurosci 1994; 3:355–363.

    Article  Google Scholar 

  134. Hamada Y, Ikata T, Katoh S, Katoh K, Niwa M, Tsutsumishita Y et al. Effects of exogenous transforming growth factor-beta 1 on spinal cord injury in rats. Neurosci Lett 1996; 203:97–100.

    Article  PubMed  CAS  Google Scholar 

  135. Baloh RH, Enomoto H, Johnson EM Jr., Milbrandt J. The GDNF family ligands and receptors Implications for neural development. Curr Op Neurobiol 2000; 10:103–110.

    Article  PubMed  CAS  Google Scholar 

  136. Airaksinen MS, Titievsky A, Saarma M. GDNF family neurotrophic factor signaling: four masters, one servant? Mol Cell Neurosci 1999;13:313–325.

    Article  PubMed  CAS  Google Scholar 

  137. Saarma M. GDNF recruits the signaling crew into lipid rafts. Trends in Neurosci 2001; 24:427–429.

    Article  CAS  Google Scholar 

  138. Gash DM, Gerhardt GA, Hoffer BJ. Effects of glial cell line-derived neurotrophic factor on the nigrostriatal dopamine system in rodents and nonhuman primates. Adv Pharmacol 1998; 42:911–5

    Article  PubMed  CAS  Google Scholar 

  139. Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson s disease. Science 2000; 290:767–773.

    Article  PubMed  CAS  Google Scholar 

  140. Kozlowski DA, Bremer E, Redmond DE Jr., George D, Larson B, Bohn MC. Quantitative analysis of transgene protein, mRNA, and vector DNA following injection of an adenoviral vector harboring glial cell line-derived neurotrophic factor into the primate caudate nucleus. Mol They 2001; 3:256–261.

    Article  CAS  Google Scholar 

  141. Iravani MM, Costa S, Jackson MI, Tel BC, Cannizzaro C, Pearce RK et al. GDNF reverses priming for dyskinesia in MPTP-treated, L-DOPA-primed common marmorsets. Eur J Neurosci 2001; 13:597–608.

    Article  PubMed  CAS  Google Scholar 

  142. Kirik D, Rosenblad C, Bjrklund A. Preservation of a functional nigrostriatal dopmaine pathway by GDNF in the intrastriatal 6-ONDA lesion model depends on the site of administration of the trophic factor. Eur J Neurosci 2000; 12:3871–3882.

    Article  PubMed  CAS  Google Scholar 

  143. Rosenblad C.. Kirik D, Bjrklund A. Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation of functional recovery in the partial 6-OHDA lesion model. Exp Neurol 2000; 161:503–516.

    Article  PubMed  CAS  Google Scholar 

  144. Choi-Lundberg DL, Lin Q, Schallert T, Crippens D, Davidson BL, Chang YN et al. Behavioral and cellular protection of rat dopmainergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. Exp Neural 1998; 154:261–275.

    Article  CAS  Google Scholar 

  145. Kirik D, Rosenblad C, Bjrklund A, Mandel RJ. Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci 2000; 20:4686–4700.

    PubMed  CAS  Google Scholar 

  146. Bensadoun JC, Deglon N, Tseng JL, Zum AD, Aebischer P. Lentiviral ectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6_OHDA model of Parkinson s disease using GDNF. Exp Neurol 2000; 164:15–24.

    Article  PubMed  CAS  Google Scholar 

  147. Bjrklund A, Kirik D, Rosenblad C, Georgievskka B, Lundberg C, Mandel RJ. Towards a neuroprotective gene therapy for Parkinson s disease: use of adenovirus, AVV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res 2000; 886:82–98.

    Article  Google Scholar 

  148. Perez-Navarro E, Akerud P, Marco S, Canals JM, Tolosa E, Arenas E et al. Neurturin protects striatal neurons but not interneurons in a rat model of Huntington s disease. Neuroscience 2000; 98:89–96.

    Article  PubMed  CAS  Google Scholar 

  149. Hottinger AF, Azzouz M, Deglon N, Aebischer P, Zum AD. Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. J Neurosci 2000; 20:5587–5593.

    PubMed  CAS  Google Scholar 

  150. Sakamoto T, Watabe K, Ohashi T, Kawazoe Y, Oyanagi K, Inoue K et al. Adenoviral vector-mediated GDNF gene transfer prevents death of adult facial motoneurons. Neuroreport 2000; 11:1857–1860.

    Article  PubMed  CAS  Google Scholar 

  151. Sakurai M, Abe K, Hayashi T, Setoguchi Y, Yaginuma G, Meguro T et al. Adenovirusmediated glial cell line-derived neurotrophic factor gene delivery reduces motor neuron injury after transient spinal cord ischemia in rabbits..J Thorac Cardiovasc Surg 2000; 120:1148–1157.

    Article  PubMed  CAS  Google Scholar 

  152. Watabe K, Sakamoto T, Ohashi T, Kawazoe Y, Oyanagi K, Takeshima T et al. Adenoviral gene transfer of glial cell line-derived neurotrophic factor to injured adult motoneurons. Hum Cell 2001; 14:7–15.

    PubMed  CAS  Google Scholar 

  153. Bilak MM, Shifrin DA, Corse AM, Bilak SR, Kuncl RW. Neuroprotective utility and neurotrophic action of neurturin in postnatal motor neurons:comparison with GDNF and persephin. Mol Cell Neurosci 1999; 13:326–336.

    Article  PubMed  CAS  Google Scholar 

  154. Kokaia Z, Airaksinen MS, Nanobashvili A, arsson E, Kujamaki E, Lindvall O et al. GDNF family ligands and receptors are differentially regulated after brain insults in the rat. Eur J Neurosci 1999; 11:1202–1216.

    Article  PubMed  CAS  Google Scholar 

  155. Miyazaki H, Okuma Y, Fujii Y, Magasima K, Nomura Y. Gleil cell line-derived neurotrophic factor protects against delayed neuronal death after transient forebrain ischemia in rats. Neuroscience 1999; 89:643–647.

    Article  PubMed  CAS  Google Scholar 

  156. Tsai TH, Chen SL, Chiang Yll, Lin SZ, Ma HI, Kuo SW et al. Recombinant adeno-associated virus vestor expressing glial cell line-derived neurotrophic factor reduces ischemiainduced damage. Exp Neurol 2000; 166:266–275.

    Article  PubMed  CAS  Google Scholar 

  157. Yagi T, Jikihara I, Fukumura M, Watanabe K, Ohashi T, Eto Y et al. Rescue of ischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils. Brain Res 2000; 885;273–283.

    Article  PubMed  CAS  Google Scholar 

  158. Nicole O, Ali C, Docagne F, Plawinski L, MacKenzie ET, Vivien D et al. Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDAinduced calcium influx by the mitogen-activated protein kinase pathway. J Neurosci 2001; 21:3024–3033.

    PubMed  CAS  Google Scholar 

  159. Lenhard, T, Schober, A., Suter-Crazzolara C, Unsicker K. Fibroblast growth factor-2 requiresglial cell line-erived neurotrophic factor for exerting its neuroprotective actions on glutamate-lesioned hippocampal neurons. Mol Cell Neurosci 2001; under revision.

    Google Scholar 

  160. Jordan J, B ttner M, Schluesener H, Unsicker K, Krieglstein K. Bone morphogenetic proteins: Neurotrophic roles for midbrain dopaminergic neurons and implications of astroglial cells. Eur J Neurosci 1997; 9:1699–1710.

    Article  PubMed  CAS  Google Scholar 

  161. Gaiter D, B ttner M, Krieglstein K, Sch mig E, Unsicker K. Differential regulation of distinct phenotypic features of serotonergic neurons by bone morphogenetic proteins. Eur J Neurosci 1999; 11:2444–2452.

    Article  Google Scholar 

  162. Hattori A, Katayama M, Iwasaki S, Ishii K, Tsujimoto M, Kohno M. Bone morphogenetic protein-2 promotes survival and differentiation of striatal GABAergic neurons in the absence of glial cell proliferation. J Neurochem 1999; 72:2264–2271.

    Article  PubMed  CAS  Google Scholar 

  163. Le Roux P, Behar S, Higgins D, Charette M. OP-1 enhamces dendritic growth from cerebral cortical neurons in vitro. Exp Neurol 1999; 160:151–163.

    Article  PubMed  Google Scholar 

  164. Reissmann E, Ernsberger U, Francis-West PH, Rueger D, Brickell PM, Rohrer H. Involvement of bone morphogenetic protein-4 and bone morphogenetic protein-7 in the differentiation of the adrenergic phenotype in developing sympathetic neurons. Development 1996; 122:2079–2088.

    PubMed  CAS  Google Scholar 

  165. Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996; 85:331–343.

    Article  PubMed  CAS  Google Scholar 

  166. Schneider C, Wicht H, Enderich J Wegner M, Rohrer H. Bone morphogenetic proteins are required in vivo for the generation of sympathetic neurons. Neuron 1999; 24:861–870.

    Article  PubMed  CAS  Google Scholar 

  167. Kobayashi M. Fujii M, Kurihara K, Matsuoka I. Bone morphogenetic protein-2 and retinoic acid induce neurotrophin-3 responsiveness in develing rat sympathetic neurons. Mol Brain Res 1998; 53:206–217.

    Article  PubMed  CAS  Google Scholar 

  168. Lopez-Coviella I, Berse B, Krauss R, Thies RS, Blusztajn JK. Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 2000; 289:313–316.

    Article  PubMed  CAS  Google Scholar 

  169. Sullivan AM, Pohl J, Blunt SB. Growth/differentiation factor 5 and glial cell line-deried neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson s disease. Eur J Neurosci 1998; 10:3681–3688.

    Article  PubMed  CAS  Google Scholar 

  170. Strelau J, Sullivan A, Bttner M, Lingor P, Falkenstein E, Suter-Crazzolara C et al. GDF15/MIC-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci 2000; 20:8597–8603.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Neuroanatomy and Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Im Neuenheimer, Feld 307, 2, OG, D-69120, Heidelberg, Germany

    Klaus Unsicker

  2. Department of Anatomy and Neuroanatomy, University ofG ttingen, Kreuzber gring 36, 0-37075, G ttingen, Germany

    Kerstin Krieglstein

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  1. Klaus Unsicker
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  1. Institute of Physiology, University of Kiel, Kiel, Germany

    Christian Alzheimer

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Unsicker, K., Krieglstein, K. (2003). TGF-ßS and Their Roles in the Regulation of Neuron Survival. In: Alzheimer, C. (eds) Molecular and Cellular Biology of Neuroprotection in the CNS. Advances in Experimental Medicine and Biology, vol 513. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0123-7_13

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