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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Oct 25;91(22):10365–10369. doi: 10.1073/pnas.91.22.10365

Disproportionate growth in mice with Igf-2 transgenes.

A Ward 1, P Bates 1, R Fisher 1, L Richardson 1, C F Graham 1
PMCID: PMC45020  PMID: 7524092

Abstract

Injection transgenesis was used to study the long-term effects of excess insulin-like growth factor II on mouse growth and differentiation. By using a construct in which the coding region of the mouse insulin like growth factor II gene (Igf-2) was placed under the control of a keratin gene promoter, four transgenic lines were established, all of which displayed overgrowth of the skin as judged by wrinkling. In addition to high levels of expression in the skin, transgene transcripts were also present in the alimentary canal and uterus. At most of the sites of transgene expression the cell number (DNA content) was greatly increased, indicating a local action of the excess insulin-like growth factor II on cell multiplication. Adult total live weight was slightly increased and there was no macroscopic evidence of tumor formation. The characteristics of these transgenic mice indicate distinct local and systemic actions for insulin-like growth factor II.

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Selected References

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  1. Adams S. O., Nissley S. P., Handwerger S., Rechler M. M. Developmental patterns of insulin-like growth factor-I and -II synthesis and regulation in rat fibroblasts. Nature. 1983 Mar 10;302(5904):150–153. doi: 10.1038/302150a0. [DOI] [PubMed] [Google Scholar]
  2. Ashton I. K., Zapf J., Einschenk I., MacKenzie I. Z. Insulin-like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy. Acta Endocrinol (Copenh) 1985 Dec;110(4):558–563. doi: 10.1530/acta.0.1100558. [DOI] [PubMed] [Google Scholar]
  3. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  4. Baker J., Liu J. P., Robertson E. J., Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993 Oct 8;75(1):73–82. [PubMed] [Google Scholar]
  5. Blessing M., Zentgraf H., Jorcano J. L. Differentially expressed bovine cytokeratin genes. Analysis of gene linkage and evolutionary conservation of 5'-upstream sequences. EMBO J. 1987 Mar;6(3):567–575. doi: 10.1002/j.1460-2075.1987.tb04792.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bondy C. A., Werner H., Roberts C. T., Jr, LeRoith D. Cellular pattern of insulin-like growth factor-I (IGF-I) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol. 1990 Sep;4(9):1386–1398. doi: 10.1210/mend-4-9-1386. [DOI] [PubMed] [Google Scholar]
  7. Carson M. J., Behringer R. R., Brinster R. L., McMorris F. A. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron. 1993 Apr;10(4):729–740. doi: 10.1016/0896-6273(93)90173-o. [DOI] [PubMed] [Google Scholar]
  8. D'Ercole A. J., Underwood L. E. Ontogeny of somatomedin during development in the mouse. Serum concentrations, molecular forms, binding proteins, and tissue receptors. Dev Biol. 1980 Sep;79(1):33–45. doi: 10.1016/0012-1606(80)90071-8. [DOI] [PubMed] [Google Scholar]
  9. Daughaday W. H., Hall K., Raben M. S., Salmon W. D., Jr, van den Brande J. L., van Wyk J. J. Somatomedin: proposed designation for sulphation factor. Nature. 1972 Jan 14;235(5333):107–107. doi: 10.1038/235107a0. [DOI] [PubMed] [Google Scholar]
  10. DeChiara T. M., Efstratiadis A., Robertson E. J. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990 May 3;345(6270):78–80. doi: 10.1038/345078a0. [DOI] [PubMed] [Google Scholar]
  11. Engström W., Rees A. R., Heath J. K. Proliferation of a human embryonal carcinoma-derived cell line in serum-free medium: inter-relationship between growth factor requirements and membrane receptor expression. J Cell Sci. 1985 Feb;73:361–373. doi: 10.1242/jcs.73.1.361. [DOI] [PubMed] [Google Scholar]
  12. Ferguson-Smith A. C., Cattanach B. M., Barton S. C., Beechey C. V., Surani M. A. Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature. 1991 Jun 20;351(6328):667–670. doi: 10.1038/351667a0. [DOI] [PubMed] [Google Scholar]
  13. Filson A. J., Louvi A., Efstratiadis A., Robertson E. J. Rescue of the T-associated maternal effect in mice carrying null mutations in Igf-2 and Igf2r, two reciprocally imprinted genes. Development. 1993 Jul;118(3):731–736. doi: 10.1242/dev.118.3.731. [DOI] [PubMed] [Google Scholar]
  14. Glasscock G. F., Hein A. N., Miller J. A., Hintz R. L., Rosenfeld R. G. Effects of continuous infusion of insulin-like growth factor I and II, alone and in combination with thyroxine or growth hormone, on the neonatal hypophysectomized rat. Endocrinology. 1992 Jan;130(1):203–210. doi: 10.1210/endo.130.1.1370151. [DOI] [PubMed] [Google Scholar]
  15. Gluckman P. D., Ambler G. R. What is the function of circulating insulin-like growth factor-2 in postnatal life? Mol Cell Endocrinol. 1993 Mar;92(1):C1–C3. doi: 10.1016/0303-7207(93)90067-t. [DOI] [PubMed] [Google Scholar]
  16. Guler H. P., Zapf J., Scheiwiller E., Froesch E. R. Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4889–4893. doi: 10.1073/pnas.85.13.4889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Henry I., Bonaiti-Pellié C., Chehensse V., Beldjord C., Schwartz C., Utermann G., Junien C. Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature. 1991 Jun 20;351(6328):665–667. doi: 10.1038/351665a0. [DOI] [PubMed] [Google Scholar]
  18. Koea J. B., Breier B. H., Shaw J. H., Gluckman P. D. A possible role for IGE-II: evidence in sheep for in vivo regulation of IGF-I mediated protein anabolism. Endocrinology. 1992 Apr;130(4):2423–2425. doi: 10.1210/endo.130.4.1547748. [DOI] [PubMed] [Google Scholar]
  19. Labarca C., Paigen K. A simple, rapid, and sensitive DNA assay procedure. Anal Biochem. 1980 Mar 1;102(2):344–352. doi: 10.1016/0003-2697(80)90165-7. [DOI] [PubMed] [Google Scholar]
  20. Lee J. E., Tantravahi U., Boyle A. L., Efstratiadis A. Parental imprinting of an Igf-2 transgene. Mol Reprod Dev. 1993 Aug;35(4):382–390. doi: 10.1002/mrd.1080350411. [DOI] [PubMed] [Google Scholar]
  21. Little M., Van Heyningen V., Hastie N. Dads and disomy and disease. Nature. 1991 Jun 20;351(6328):609–610. doi: 10.1038/351609a0. [DOI] [PubMed] [Google Scholar]
  22. Liu J. P., Baker J., Perkins A. S., Robertson E. J., Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993 Oct 8;75(1):59–72. [PubMed] [Google Scholar]
  23. Mathews L. S., Hammer R. E., Behringer R. R., D'Ercole A. J., Bell G. I., Brinster R. L., Palmiter R. D. Growth enhancement of transgenic mice expressing human insulin-like growth factor I. Endocrinology. 1988 Dec;123(6):2827–2833. doi: 10.1210/endo-123-6-2827. [DOI] [PubMed] [Google Scholar]
  24. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
  26. Moses A. C., Nissley S. P., Short P. A., Rechler M. M., White R. M., Knight A. B., Higa O. Z. Increased levels of multiplication-stimulating activity, an insulin-like growth factor, in fetal rat serum. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3649–3653. doi: 10.1073/pnas.77.6.3649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nagarajan L., Nissley S. P., Rechler M. M., Anderson W. B. Multiplication-stimulating activity stimulates the multiplication of F9 embryonal carcinoma cells. Endocrinology. 1982 Apr;110(4):1231–1237. doi: 10.1210/endo-110-4-1231. [DOI] [PubMed] [Google Scholar]
  28. Nissley P., Kiess W., Sklar M. Developmental expression of the IGF-II/mannose 6-phosphate receptor. Mol Reprod Dev. 1993 Aug;35(4):408–413. doi: 10.1002/mrd.1080350415. [DOI] [PubMed] [Google Scholar]
  29. Ogawa O., Eccles M. R., Szeto J., McNoe L. A., Yun K., Maw M. A., Smith P. J., Reeve A. E. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature. 1993 Apr 22;362(6422):749–751. doi: 10.1038/362749a0. [DOI] [PubMed] [Google Scholar]
  30. Quaife C. J., Mathews L. S., Pinkert C. A., Hammer R. E., Brinster R. L., Palmiter R. D. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology. 1989 Jan;124(1):40–48. doi: 10.1210/endo-124-1-40. [DOI] [PubMed] [Google Scholar]
  31. Rainier S., Johnson L. A., Dobry C. J., Ping A. J., Grundy P. E., Feinberg A. P. Relaxation of imprinted genes in human cancer. Nature. 1993 Apr 22;362(6422):747–749. doi: 10.1038/362747a0. [DOI] [PubMed] [Google Scholar]
  32. Rathjen P. D., Nichols J., Toth S., Edwards D. R., Heath J. K., Smith A. G. Developmentally programmed induction of differentiation inhibiting activity and the control of stem cell populations. Genes Dev. 1990 Dec;4(12B):2308–2318. doi: 10.1101/gad.4.12b.2308. [DOI] [PubMed] [Google Scholar]
  33. Rogler C. E., Yang D., Rossetti L., Donohoe J., Alt E., Chang C. J., Rosenfeld R., Neely K., Hintz R. Altered body composition and increased frequency of diverse malignancies in insulin-like growth factor-II transgenic mice. J Biol Chem. 1994 May 13;269(19):13779–13784. [PubMed] [Google Scholar]
  34. Rotwein P., Hall L. J. Evolution of insulin-like growth factor II: characterization of the mouse IGF-II gene and identification of two pseudo-exons. DNA Cell Biol. 1990 Dec;9(10):725–735. doi: 10.1089/dna.1990.9.725. [DOI] [PubMed] [Google Scholar]
  35. Schofield P. N., Lee A., Hill D. J., Cheetham J. E., James D., Stewart C. Tumour suppression associated with expression of human insulin-like growth factor II. Br J Cancer. 1991 May;63(5):687–692. doi: 10.1038/bjc.1991.156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Skottner A., Clark R. G., Fryklund L., Robinson I. C. Growth responses in a mutant dwarf rat to human growth hormone and recombinant human insulin-like growth factor I. Endocrinology. 1989 May;124(5):2519–2526. doi: 10.1210/endo-124-5-2519. [DOI] [PubMed] [Google Scholar]
  37. Werner H., Woloschak M., Adamo M., Shen-Orr Z., Roberts C. T., Jr, LeRoith D. Developmental regulation of the rat insulin-like growth factor I receptor gene. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7451–7455. doi: 10.1073/pnas.86.19.7451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Werner S., Weinberg W., Liao X., Peters K. G., Blessing M., Yuspa S. H., Weiner R. L., Williams L. T. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 1993 Jul;12(7):2635–2643. doi: 10.1002/j.1460-2075.1993.tb05924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wilson D. M., Thomas J. A., Hamm T. E., Jr, Wyche J., Hintz R. L., Rosenfeld R. G. Transplantation of insulin-like growth factor-II-secreting tumors into nude rodents. Endocrinology. 1987 May;120(5):1896–1901. doi: 10.1210/endo-120-5-1896. [DOI] [PubMed] [Google Scholar]
  40. van Buul-Offers S., Hoogerbrugge C. M., Branger J., Feijlbrief M., Van den Brande J. L. Growth-stimulating effects of somatomedin-/insulin-like peptides in Snell dwarf mice. Horm Res. 1988;29(5-6):229–236. doi: 10.1159/000181009. [DOI] [PubMed] [Google Scholar]

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