The GH/IGF-1 Axis: Insights from Animal Models

  • Martin Holzenberger
  • Laurent Kappeler
  • Carlos De Magalhaes Filho
  • Yves Le Bouc
Part of the Research and Perspectives in Endocrine Interactions book series (RPEI)

Summary

Individuals develop from single cells through a genetically controlled program that regulates cell growth, cell proliferation and differentiation. The quantitative equilibrium between cell differentiation and proliferation is particularly important for tissue-specific growth and the shaping of higher organisms. Insulin-like growth factors (IGF) are key regulators of somatic growth, and growth hormone (GH), by controlling important aspects of IGF activity in many tissues in mammals, is able to coordinate this growth in a defined, spatio-temporal manner at the whole body level. Using homologous recombination, we generated mouse models with genetically determined IGF-1R insufficiency. We showed that partial inactivation of IGF-1R causes postnatal growth deficits that appear during the postnatal growth spurt and persist in the adult. We found that these growth deficits depend on the dosage of the IGF-1R gene. In our mutant mice, the postnatal growth of males relied more strongly on IGF-1R levels than the growth of females. Experiments using tissue-specific IGF-1R inactivation in the central nervous system provided evidence that IGF signaling in the brain may play a key role during the development of the somatotrope function in mammals.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfäffle R, Raile K, Seidel B, Smith RJ, Chernausek SD (2003) IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. New Engl J Med 349: 2211–2222CrossRefPubMedGoogle Scholar
  2. Baker J, Liu J-P, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82CrossRefPubMedGoogle Scholar
  3. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384: 33CrossRefPubMedGoogle Scholar
  4. Cadoret A, Desbois-Mouthon C, Wendum D, Leneuve P, Perret C, Tronche F, Housset C, Holzenberger M (2005) c-Myc-induced hepatocarcinogenesis in the absence of insulin-like growth factor 1 receptor. Int J Cancer 114: 668–672CrossRefPubMedGoogle Scholar
  5. Coschigano KT, Clemmons D, Bellushi LL, Kopchick JJ (2000) Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 141: 2608–2613CrossRefPubMedGoogle Scholar
  6. Denley A, Wang CC, McNeil KA, Walenkamp MJE, van Duyvenvoorde H, Wit JM, Wallace JC, Norton RS, Karperien M, Forbes BE (2005) Structural and functional characteristics of the Val44Met IGF-I missense mutation: correlation with effects on growth and development. Mol Endocrinol 19: 711–721PubMedGoogle Scholar
  7. Dupont J, Holzenberger M (2003) Biology of insulin-like growth factors in development. Birth Defects Res (Part C) 69: 257–271CrossRefGoogle Scholar
  8. Flurkey K, Papaconstantinou J, Miller RA, Harrison DE (2001) Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 9: 6736–6741Google Scholar
  9. Gems D, Partridge L (2001) Insulin/IGF signalling and ageing: seeing the bigger picture. Curr Opin Genet Dev 11: 287–292CrossRefPubMedGoogle Scholar
  10. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408: 255–262CrossRefPubMedGoogle Scholar
  11. Holzenberger M (2004) The GH/IGF-1 axis and longevity. Eur J Endocrinol 151,suppl 1: S23–27PubMedGoogle Scholar
  12. Holzenberger M, Martín-Crespo RM, Vicent D, Ruiz-Torres A (1991) Decelerated growth and longevity in men. Arch Gerontol Geriat 13: 89–101Google Scholar
  13. Holzenberger M, Lenzner C, Leneuve P, Zaoui R, Hamard G, Vaulont S, Le Bouc Y (2000a) Cremediated germ-line mosaicism: a method allowing rapid generation of several alleles of a target gene. Nucleic Acids Res 28: e92CrossRefPubMedGoogle Scholar
  14. Holzenberger M, Leneuve P, Hamard G, Ducos B, Périn L, Binoux M, Le Bouc Y (2000b) A targeted partial invalidation of the IGF-I receptor gene in mice causes a postnatal growth deficit. Endocrinology 141: 2557–2566CrossRefPubMedGoogle Scholar
  15. Holzenberger M, Hamard G, Zaoui R, Leneuve P, Ducos B, Beccavin C, Périn L, Le Bouc Y (2001) IGF-I receptor gene dosage generates a sexually dimorphic pattern of organ-specific growth deficits, affecting fat tissue in particular. Endocrinology 142: 4469–4478CrossRefPubMedGoogle Scholar
  16. Holzenberger M, Dupont J, Ducos B, Leneuve P, Géloën A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates life span and resistance to oxidative stress in mice. Nature 421: 182–187CrossRefPubMedGoogle Scholar
  17. Hwa V, Oh Y, Burren CP, Choi WK, Graham DL, Ingermann A, Kim H-S, Lopez-Bermejo, Minniti G, Nagalla SR, Pai K, Spagnoli A, Vorwerk P, Wanek DLV, Wilson EM, Yamanaka Y, Yang DH, Rosenfeld RG (1999) The IGF binding protein superfamily. In: Rosenfeld RG, Roberts CT (eds) The IGF system. Humana Press, Totowa, NJ, pp. 315–328Google Scholar
  18. Kenyon C (2001) A conserved regulatory system for aging. Cell 105: 165–168CrossRefPubMedGoogle Scholar
  19. Kondo T, Vicent D, Suzuma K, Yanagisawa M, King GL, Holzenberger M, Kahn CR (2003) Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. J Clin Invest 111: 1835–1842CrossRefPubMedGoogle Scholar
  20. Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR (2002) β-cell-specific deletion of the Igf-1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nature Genet 31: 111–115PubMedGoogle Scholar
  21. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75: 59–72CrossRefPubMedGoogle Scholar
  22. Lupu L, Terwilliger JD, Lee K, Segre GV, Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229, 141–162CrossRefPubMedGoogle Scholar
  23. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. (1999) The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309–313PubMedGoogle Scholar
  24. Murakami S, Salmon A, Miller RA (2003) Multiplex stress resistance in cells from long-lived dwarf mice. FASEB J 17: 1565–1566PubMedGoogle Scholar
  25. Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424: 277–283CrossRefPubMedGoogle Scholar
  26. Nakae J, Kido Y, Accili D (2001) Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 22: 818–835CrossRefPubMedGoogle Scholar
  27. Sjogren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Tornell J, Isaksson OG, Jansson JO, Ohlsson C (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA 96: 7088–7092CrossRefPubMedGoogle Scholar
  28. Tseng YH, Ueki K, Kriauciunas KM, Kahn CR (2002) Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. J Biol Chem 277: 31601–31611PubMedGoogle Scholar
  29. Tseng YH, Kriauciunas KM, Kokkotou E, Kahn CR (2004) Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol 24: 1918–1929CrossRefPubMedGoogle Scholar
  30. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzelli LM, Dull TJ, Gray A, Coussens L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313: 756–761CrossRefPubMedGoogle Scholar
  31. Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E, Jacobs S, Francke U, Ramachandran J, Fujita-Yamaguchi Y (1986) Insulin-like growth factor-I receptor primary structure: Comparison with insulin receptor suggests structural determinants that define functional specificity. EMBO J 5: 2503–2512PubMedGoogle Scholar
  32. Woods KA, Camacho-Hübner C, Savage MO, Clark AJ (1996) Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. New Engl J Med 335: 1363–1367CrossRefPubMedGoogle Scholar
  33. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 96:7324–7329CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Martin Holzenberger
    • 1
  • Laurent Kappeler
    • 1
  • Carlos De Magalhaes Filho
    • 1
  • Yves Le Bouc
    • 1
  1. 1.Inserm U515, Hôpital Saint-AntoineParisFrance

Personalised recommendations