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Accelerated growth and visceral lesions in transgenic mice expressing foreign genes of the growth hormone family: an overview

  • Endocrine Changes Review Article
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Abstract

Effects of growth hormone (GH) overproduction were studied in transgenic mice expressing murine metallothionein I-GH fusion genes. The most obvious consequence was the acceleration of growth, which led to substantial increases in body weight of up to more than twice that seen in controls. Growth of the internal organs was stimulated, with hepatomegaly and nephromegaly as the most prominent features. GH transgene expression was also reflected in increased skeletal growth which affected various bones to different extents. The mean life-span of human GH transgenic mice with serum levels of hGH ranging from 3×103 to 9×105 ng/ml was drastically reduced at 160 days in both sexes. Severe renal lesions were the primary cause of the decrease in life expectancy and were characterized by marked nephron atrophy, obsolescence of numerous glomeruli, and a massive cystic dilation of the tubules. Initial changes involved the glomeruli, which showed significant enlargement and sclerotic lesions. The liver exhibited a pronounced hepatocellularmegaly and progressive degenerative as well as hyperplastic changes. One-third of the hGH transgenic animals displayed myocardial fibrosis. Hepatocellylar carcinoma was found in bovine GH transgenic mice older than 12 months. Our observations are compared with results of other investigators.

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References

  1. Gordon JW, Scangos GA, Plotkin DJ, Barbosa A, Ruddle FH (1980) Genetic transformation of mouse embryos by microinjection. Proc Natl Acad Sci USA 77:7380–7384

    PubMed  Google Scholar 

  2. Palmiter RD, Brinster RL (1985) Transgenic mice. Cell 41:343–345

    PubMed  Google Scholar 

  3. Cuthbertson RA, Klintworth GK (1988) Transgenic mice — a gold mine for furthering knowledge in pathobiology. Lab Invest 58:484–502

    PubMed  Google Scholar 

  4. Jaenisch R, Mintz B (1974) Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proc Natl Acad Sci USA 71:1250–1254

    PubMed  Google Scholar 

  5. Hammer RE, Pursel VG, Rexroad CE Jr, Wall RJ, Bolt DJ, Ebert KM, Palmite RD, Brinster RL (1985) Production of transgenic rabbits, sheep and pigs by microinjection. Nature 315:680–683

    PubMed  Google Scholar 

  6. Brem G, Brenig B, Goodman HM, Selden RC, Graf F, Kruff B, Springmann K, Hondele J, Meyer J, Winnacker EL, Kräusslich H (1985) Production of transgenic mice, rabbits and pigs by microinjection into pronuclei. Zuchthygiene 20:251–252

    Google Scholar 

  7. Brem G (1990) Transgenic mice as disease models. Arzneimittelforsch (Drug Res) 40:335–343

    Google Scholar 

  8. Palmiter RD, Brinster RL (1986) Germ-line transformation of mice. Annu Rev Genet 20: 465–499

    PubMed  Google Scholar 

  9. Costantini F, Lacy E (1981) Introduction of a rabbit β-globulin gene into the mouse germ line. Nature 294: 92–94

    PubMed  Google Scholar 

  10. Brinster RL, Chen HY, Trumbauer ME, Yagle MK, Palmiter RD (1985) Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci USA 82: 4438–4442

    PubMed  Google Scholar 

  11. Hogan B, Costantini F, Lacy E (1986) Manipulating the mouse embryo. Cold Spring Harbor Laboratory, New York

    Google Scholar 

  12. DePamphilis ML, Herman SA, Martinez-Salas E, Chalifour LE, Wirak DO, Cupo DY, Miranda M (1988) Microinjecting DNA into mouse ova to study DNA replication and gene expression and to produce transgenic animals. BioTechniques 6: 662–679

    PubMed  Google Scholar 

  13. Gordon JW, Ruddle FH (1983) Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection. Methods Enzymol 101: 411–433

    PubMed  Google Scholar 

  14. Hammer RE, Brinster RL, Palmiter RD (1985) Use of gene transfer to increase animal growth. Cold Spring Harb Symp Quant Biol 50: 379–387

    PubMed  Google Scholar 

  15. Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC, Evans RM (1982) Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature 300: 611–615

    PubMed  Google Scholar 

  16. Kägi JHR, Nordberg M (eds) (1979) Metallothionein. Birkhäuser, Basel

    Google Scholar 

  17. Cherian MG, Goyer RA (1978) Metallothioneins and their role in the metabolism and toxicity of metals. Life Sci 23: 1–10

    PubMed  Google Scholar 

  18. Palmiter RD, Norstedt G, Gelinas RE, Hammer RE, Brinster RL (1983) Metallothionein-human GH fusion genes stimulate growth of mice. Science 222: 809–814

    PubMed  Google Scholar 

  19. Swanson LW, Simmons DM, Arriza J, Hammer R, Brinster R, Rosenfeld MG, Evans RM (1985) Novel developmental specificity in the nervous system of transgenic animals expressing growth hormone fusion genes. Nature 317: 363–366

    PubMed  Google Scholar 

  20. Hammer RE, Palmiter RD, Brinster RL (1984) Partial correction of murine hereditary growth disorder by germ-line incorporation of a new gene. Nature 311: 65–67

    PubMed  Google Scholar 

  21. Behringer RR, Mathews LS, Palmiter RD, Brinster RL (1988) Dwarf mice produced by genetic ablation of growth hormone-epressing cells. Genes Dev 2: 453–461

    PubMed  Google Scholar 

  22. Dudley GA, Portanova R (1987) Histochemical characteristics of soleus muscle in hGH transgenic mice. Proc Soc Exp Biol Med 185: 403–408

    PubMed  Google Scholar 

  23. Bartke A, Steger RW, Hodges SL, Parkening TA, Collins TJ, Yun JS, Wagner TE (1988) Infertility in transgenic female mice with human growth hormone expression: evidence for luteal failure. J Exp Zool 248: 121–124

    PubMed  Google Scholar 

  24. Brem G, Wanke R, Wolf E, Buchmüller T, Müller M, Brenig B, Hermanns W (1989) Multiple consequences of human growth hormone expression in transgenic mice. Mol Biol Med 6: 531–547

    PubMed  Google Scholar 

  25. Celniker AC, Chen AB, Wert RM Jr, Sherman BM (1989) Variablity in the quantitation of circulating growth hormone using commercial immunoassays. J Clin Endocrinol Metab 68: 469–476

    PubMed  Google Scholar 

  26. Wolf E, Brem G (1989) A comparison of different immunoradiometric assays for detecting hGH in the serum of MT-hGH transgenic mice and controls. Acta Endocrinol (Copenh) [Suppl] 120: 143–144

    Google Scholar 

  27. Hammer RE, Brinster RL, Rosenfeld MG, Evans RM, Mayo KE (1985) Expression of human growth hormone-releasing factor in transgenic mice results in increased somatic growth. Nature 315: 413–416

    PubMed  Google Scholar 

  28. Shea BT, Hammer RE, Brinster RL (1987) Growth allometry of the organs in giant transgenic mice. Endocrinology 121: 1924–1930

    PubMed  Google Scholar 

  29. Miller KF, Bolt DJ, Pursel VG, Hammer RE, Pinkert CA, Palmiter RD, Brinster RL (1989) Expression of human or bovine growth hormone gene with a mouse metallothionein-I promoter in transgenic swine alters the secretion of porcine growth hormone and insulin-like growth factor-I. J Endocrinol 120: 481–488

    PubMed  Google Scholar 

  30. Vize PD, Michalska AE, Ashman R, Lloyd B, Stone BA, Quinn P, Wells JRE, Scamark RF, (1988) Introduction of a porcine growth hormone fusion gene into transgenic pigs promotes growth. J Cell Sci 90: 295–300

    PubMed  Google Scholar 

  31. Quaife CJ, Mathews LS, Pinkert CA, Hammer RE, Brinster RL, Palmiter RD (1989) Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124: 40–48

    PubMed  Google Scholar 

  32. Orian JM, Lee CS, Weiss LM, Brandon MR (1989) The expression of a metallothionein-ovine growth hormone fusion gene in transgenic mice does not impair fertility but results in pathological lesions in the liver. Endocrinology 124: 455–463

    PubMed  Google Scholar 

  33. Mayerhofer A, Weis J, Bartke A, Wagner TE (1990) Effects of transgenes for human and bovine growth hormones on age-related changes in ovarian morphology in mice. Anat Rec 227: 175–186

    PubMed  Google Scholar 

  34. Mathews LS, Hammer RE, Behringer RR, D'Ercole AJ, Bell GI, Brinster RL, Palmiter RD, (1988) Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology 123: 2827–2833

    PubMed  Google Scholar 

  35. Doi T, Striker LJ, Quaife C, Conti FG, Palmiter R, Behringer R, Brinster R, Striker GE (1988) Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor but not in those expressing insulinlike growth factor-1. Am J Pathol 131: 398–403

    PubMed  Google Scholar 

  36. Olson JL, Urdaneta AG de, Heptinstall RH (1985) Glomerular hyalinosis and its relation to hyperfiltration. Lab Invest 52: 387–398

    PubMed  Google Scholar 

  37. Striker LJ, Doi T, Striker GE, (1990) Utilisation des animaux transgéniques en recherche néphrologique. In: Hamberger J (ed) Actualités néphrologiques. Flamarion Paris, pp 93–106

    Google Scholar 

  38. Brem G, Wanke R (1988) Phenotypic and pathomorphological characteristics in a half-sib-family of transgenic mice carrying foreign MT-hGH genes. In: Beynen AG, Solleveld HA (eds) New developments in biosciences: their implications for laboratory animal science. Martinus Nijhoff, Dordrecht, pp 93–98

    Google Scholar 

  39. Orian JM, Tamakoshi K, Mackey IR, Brandon MR (1990) New murine model for hepatocellular carcinoma: transgenic mice expressing metallothionein-ovine growth hormone fusion genes. J Natl Cancer Inst 82: 393–398

    PubMed  Google Scholar 

  40. Messing A, Chen HY, Palmiter RD, Brinster RL (1985) Peripheral neuropathies, hepatocellular carcinomas and islet cell adenomas in transgenic mice. Nature 316: 461–463

    PubMed  Google Scholar 

  41. Dilley RJ, Schwartz SM (1989) Vascular remodeling in the growth hormone transgenic mouse. Circ Res 65: 1233–1240

    PubMed  Google Scholar 

  42. Selden RF, Yun JS, Moore DD, Rowe ME, Malia MA, Wagner TE, Goodman H (1989) Glucocorticoid regulation of human growth hormone expression in transgenic mice and transiently transfected cells. J Endocrinol 122: 49–60

    PubMed  Google Scholar 

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Wanke, R., Hermanns, W., Folger, S. et al. Accelerated growth and visceral lesions in transgenic mice expressing foreign genes of the growth hormone family: an overview. Pediatr Nephrol 5, 513–521 (1991). https://doi.org/10.1007/BF01453693

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  • DOI: https://doi.org/10.1007/BF01453693

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