MMTV/N-ras Transgenic Mice as a Model for Altered Capacitation Male Sterility and Tumorigenesis

  • Ramon Mangues
  • Irving Seidman
  • Angel Pellicer
  • Jon W. Gordon


Infertility is generally defined as a failure to conceive following one year of unprotected intercourse; it affects about 10% to 15% of couples attempting a pregnancy for the first time (Romeny et al., 1975). Abnormalities in the male partner contribute to infertility in about 40% of these couples (Speroff et al., 1983).


Transgenic Mouse Male Sterility Submaxillary Gland Male Infertility Mouse Mammary Tumor Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aitken, R.J., Best, F.S.M., and Wagner, P., 1984, A prospective study of the relationship between semen quality and fertility in cases of unexplained infertility, J. Androl., 5:297–303.PubMedGoogle Scholar
  2. Aitken, R.J., 1985, Diagnostic value of the zona-free hamster oocyte penetration test and sperm movement characteristics in oligozoospermia, Int. J. Androl., 8:348–356.PubMedCrossRefGoogle Scholar
  3. Al-Shawi, R., Burke, J., Jones, C.T., Simons, J.P., and Bishop, J.O., 1988, A Mup promoterthymidine kinase reporter gene shows relaxed tissue-specific expression and confers male sterility upon transgenic mice, Mol. Cell Biol. 8(11):4821–4828.PubMedGoogle Scholar
  4. Ausubel, F.M., Brent, R., Kingston, R.E., Moore, D.D., Seidman, J.G., Smith, J.A., and Struhl, J., (eds) 1989, Current Protocols in Molecular Biology, Greene Publishing Associates and Willey-Interscience, New York.Google Scholar
  5. Bardin, C.W., Musto, N., Gunsalus, G., Kotite, N., Cheng, S.-L., Larrea, F., and Becker, R., 1981, Extracellular androgen binding proteins, Ann. Rev. Physiol., 43:189–198.CrossRefGoogle Scholar
  6. Bautch, V.L., Toda, S., Hassell, J.A., and Hanahan, D., 1987, Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene, Cell, 51:529–538.PubMedCrossRefGoogle Scholar
  7. Behringer, R.R., Peschon, J.J., Messing, A., Gartside, C.L., and Hauschka, S.D., 1988, Heart and bone tumors in transgenic mice, Proc. Natl. Acad. Sci., USA, 85:2648–2652.PubMedCrossRefGoogle Scholar
  8. Bos, J.L., 1989, ras oncogenes in human cancer: a review, Cancer Res., 49:4682–4689.PubMedGoogle Scholar
  9. Bouchard, L., Lamarre, L., Tremblay, P.J., and Jolicoeur, P., 1989, Stochoastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene, Cell, 57:931–936.PubMedCrossRefGoogle Scholar
  10. Brooks, D.E., 1987, Androgen-regulated epididymal secretory proteins associated with posttesticular sperm development, In: Orbegin-Crist M.-C., and Danzo, B.J., eds., Ann. N.Y. Acad. Sci., 513:179–194.Google Scholar
  11. Chirgwin, J.J., Przbyla, A.E., MacDonald, R.J., and Rutter, W.J., 1979. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease, Biochemistry, 18:5294–5299.PubMedCrossRefGoogle Scholar
  12. Choi, Y., Henrard, D., Lee, I., and Ross, S.R., 1987, The mouse mammary tumor virus long terminal repeat directs expression in epithelial and lymphoid cells of different tissues in transgenic mice, J. Virol., 61:3013–3019.PubMedGoogle Scholar
  13. Choi, Y., Lee, I., and Ross, S.R., 1988, Requirement for simian virus 40 small tumor antigen in tumorigenesis in transgenic mice, Mol. Cell Biol., 8(8)3382–3390.PubMedGoogle Scholar
  14. Darbre, P., Page, M., and King, R.J.B., 1986, Androgen regulation by the long terminal repeat of mouse mammary tumor virus, Mol. Cell Biol., 6:2847–2854.PubMedGoogle Scholar
  15. DeFeo, D., Gonda, M.A., Young, H.A., Chang, E.H., Lowy, D.R., Scolnick, E.M., and Ellis, R.W., 1981, Analysis of two divergent rat genomic clones homologous to the transforming gene of Harvey murine sarcoma virus. Proc. Natl. Acad. Sci., USA, 78:3328–3332.PubMedCrossRefGoogle Scholar
  16. Ellis, R.W., DeFeo, D., Shih, T.Y., Gonda, M.A., Young, H.A., Tsuchida, N., Lowy, D.R., and Scolnick, E., 1981, The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes, Nature, 292:506–511.PubMedCrossRefGoogle Scholar
  17. Ewing, L.L., and T.S.K. Chang, 1986, The testis, epididymis, and ductus deferens, in: “Campbell’s Urology,” 5th ed. vol. 1, P.C. Walsh, R.F. Gittes, A.D. Perlmutter, and T.A. Stamey, eds., W.B. Saunders Company, Philadelphia, 200–233.Google Scholar
  18. Feinberg, A.P., and Vogelstein, B., 1984, A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity, Anal. Biochem, 137:266–267.PubMedCrossRefGoogle Scholar
  19. Gordon, J.W., 1986, A foreign dihydrofolate reductase gene in transgenic mice acts as a dominant mutation, Mol. Cell Biol., 6:258–267.Google Scholar
  20. Gordon, J.W., and Ruddle, F.H., 1981, Integration and stable germ line transmission of genes injected into mouse pronuclei, Science, 214: 1244–1246.PubMedCrossRefGoogle Scholar
  21. Gordon, J.W., and Ruddle, F.H., 1983, Gene transfer into mouse embryos: production of transgenic mice by pronuclear injection, Meth. Enzymol., 101:411–433.PubMedCrossRefGoogle Scholar
  22. Gordon, J.W., Scangos, G.A., Plotkin, D.J., Barbosa, J.A., and Ruddle, F.H., 1980, Genetic transformation of mouse embryos by microinjection of purified DNA, Proc. Natl. Acad. Sci. USA, 77:7380–7384.PubMedCrossRefGoogle Scholar
  23. Gordon, J.W., and Talansky, B.E., 1986, Assisted fertilization by zona drilling: a mouse model for correction of oligospermia, /. Exp. Zool., 239:347–354.CrossRefGoogle Scholar
  24. Guerrero, I., Pellicer, A., and Burstein, D.E., 1988, Dissociation of c-fos from ODC expression and neuronal differentiation in a PC 12 subline stably transfected with a inducible N-ras oncogene, Biochem. Biophys. Res. Com., 150:1185–1192.PubMedCrossRefGoogle Scholar
  25. Guerrero, I., Villasante, A., D’Eustachio, P., and Pellicer, A., 1984, Isolation, characterization, and chromosome assignment of mouse N-ras gene from carcinogen-induced thymic lymphoma, Science, 225 (4666) 1041–1043.PubMedCrossRefGoogle Scholar
  26. Holland, M.K., and Orbegin-Crist, M.-C., 1988a, Characterization and hormonal regulation of protein synthesis by the murine epididymis, Biol. Reprod., 38:487–496.PubMedCrossRefGoogle Scholar
  27. Holland, M.K., and M.-C. Orbegin-Crist, 1988b, Epididymal protein synthesis and secretion in strains of mice bearing single gene mutations which affect fertility, Biol. Reprod., 38:497–510.PubMedCrossRefGoogle Scholar
  28. Hsu, T.W., Sabran, J.L., Mark, G.E., Guntaka, R.N., and Taylor, J.M., 1978, Analysis of unintegrated avian RNA tumor virus double-stranded DNA intermediate, J. Virol., 28:810–818.PubMedGoogle Scholar
  29. Hynes, N.E., Groner, B., and Michalides, R., 1984, Mouse mammary tumor virus: transcriptional control and involvement in tumorigenesis, Adv. Cancer Res., 41:155–184.PubMedCrossRefGoogle Scholar
  30. Imai, S., Morimoto, J., Tsubura, Y., Iwai, Y., Okumoto, M., Takamori, Y., Tsubura, A., and Hilgers, J., 1983, Tissue and organ distribution of mammary tumor virus antigens in low and high mammary cancer strain mice, Eur. J. Cancer Clin. Oncol., 19(7) 1011–1019.PubMedCrossRefGoogle Scholar
  31. Iwakura, Y., Asano, M., Nishimune, Y., and Kawade, Y., 1988, Male sterility of transgenic mice carrying exogenous mouse interferon-b gene under the control of the metallothionein enhancerpromoter, EMBO J., 7(12)3757–3762.PubMedGoogle Scholar
  32. Leder, A., Pattengale, K., Kuo, A., Stewart, T.A., and Leder, P., 1986, Consequence of widespread deregulation of the c-myc gene in transgenic mice: multiple neoplasm and normal development, Cell, 45:485–495.PubMedCrossRefGoogle Scholar
  33. Leon, J., Guerrero, I., and Pellicer, A., 1987, Differential expression of the ras gene family in mice, Mol. Cell Biol., 7:1535–1540.PubMedGoogle Scholar
  34. Moore, H.D., and Bedford, J.M., 1983, The interaction of mammalian gametes in the female, In: “Mechanism and Control of Animal Fertilization”, Hartmann, J.F., ed., Academic Press, New York, 453.Google Scholar
  35. Muller, W.J., Sinn, E., Pattengale, P.K., Wallace, R., and Leder, P., 1988, Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene, Cell 54:105–115.PubMedCrossRefGoogle Scholar
  36. Orbegin-Crist, M.-C., 1969, Studies on the function of the epididymis, Biol. Reprod. (Suppl.), 1:155–160.CrossRefGoogle Scholar
  37. Orbegin-Crist, M.-C., and Fournier-Delpech, 1982, Sperm-egg interaction, Evidence for maturational changes during epididymal transit, J. Androl, 3:429–433.Google Scholar
  38. Otten, A.D., Sanders, M.M., and G.S. McKnight, 1988, The MMTV LTR promoter is induced by progesterone and dihydrotestosterone but not by estrogen, Mol Endocrinol, 2:143–147.PubMedCrossRefGoogle Scholar
  39. Propst, F., Rosenberg, M.P., and Van de Woude, G.F., 1988a, Proto-oncogene expression in germ cell development, Trends in Genetics, 4(7): 183–187.PubMedCrossRefGoogle Scholar
  40. Propst, F., Rosenberg, M.P., Oskarsson, M.K., Russel, L.B., Nguyen-Huu, M.C., Nadeau, J., Jenkins, N.A., Copeland, N.G., and Van de Woude, G.F., 1988b, Genetic analysis and development regulation of testis-specific RNA expression of mos, abl, actin and Hox-1.4, Oncogene, 2:227–233.PubMedGoogle Scholar
  41. Quinn, P., Barros, C., and Whittingham, D.H., 1982, Preservation of hamster oocytes to assay the fertilizing capacity of human spermatozoa, J. Reprod. Fert., 66:161–168.CrossRefGoogle Scholar
  42. Rigby, P.W.J., Dieckmann, M., Rhodes, C., and Berg, P., 1977, Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA Polymerase I, J. Mol Biol, 113:237–251.PubMedCrossRefGoogle Scholar
  43. Romeny, S., Gray, M.J., Little, B., 1975, The Health Care of Women in Gynecology and Obstetrics, McGraw-Hill, New York, 345.Google Scholar
  44. Ross, S.R., and Solter, D., 1985, Glucocorticoid regulation of mouse mammary tumor virus sequences in transgenic mice, Proc. Natl Acad. Sci. USA, 82:5880–5884.PubMedCrossRefGoogle Scholar
  45. Shackleford, G.M., and Varmus, H.E., 1987, Expression of the proto-oncogene int-1 is restricted to postmeiotic male germ cells and the neural tube of mid-gestational embryos, Cell, 50:89–95.PubMedCrossRefGoogle Scholar
  46. Sherins, R.J., and Howards, S.S., 1986, Male Sterility, In: “Campbell’s Urology,” 5th ed. vol. 1, Walsh, P.C., Gittes, R.F., Perlmutter, A.D., and Stamey, T.A., eds., Saunders Company, Philadelphia, 640–697.Google Scholar
  47. Shimizu, K., Goldfarb, M., Perucho, M., and Wigler, M., 1983, Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line, Proc. Natl Acad. Sci. USA, 80:383–387.PubMedCrossRefGoogle Scholar
  48. Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R., and Leder, P., 1987, coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo, Cell, 49:465–475.PubMedCrossRefGoogle Scholar
  49. Smith, D., Rodriguez-Rigau, L.J., and Steinberger, E., 1977, Relation between indices of semen analysis and pregnancy rate in infertile couples, Fertil Steril, 28:1314–1319.PubMedGoogle Scholar
  50. Smith, R.G., Johnson, A., Lamb, D., and Lipshultz, L.L., 1987, Functional tests of spermatozoa. Sperm penetration assay. Urologic Clinics of North America, 14:451–458.Google Scholar
  51. Sorrentino, V., McKinney, M.D., Giorgi, M., Geremia, R., and Fleissner, E., 1988, Expression of cellular protooncogenes in the mouse male germ line: A distinctive 2.4-kilobase pim-1 transcript is expressed in haploid postmeiotic cells, Proc. Natl Acad. Scie. USA, 85:2191–2195.CrossRefGoogle Scholar
  52. Speroff, L., Glass, R.H., and Kase, N.G., 1983, Clinical Gynecologic Endocrinology and Infertility, Williams and Wilkins, Baltimore, 173.Google Scholar
  53. Stewart, T.A., Pattengale, P.K., and Leder, P., 1984, Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes, Cell, 38:627–637.PubMedCrossRefGoogle Scholar
  54. Tezon, J.G., Vazquez, M.H., De Larminat, M.A., Cameo, M.S., Pineiro, L., Piazza, A., Scorticati, C., and Blaquier, J., 1987, Further characterization of a model system for the study of human epididymal physiology and its relation to sperm maturation, In: Orbegin-Crist, M.-C., and B.J. Danzo, eds., Ann. N.Y. Acad. Sci., 513:215–221.Google Scholar
  55. Thadani, V.M. 1982, Mice produced from eggs fertilized in vitro at a very low sperm:egg ratio, J. Exp. Zool., 219:277–283.PubMedCrossRefGoogle Scholar
  56. Tremblay, P.J., Pothier, F., Hoang, T., Tremblay, G., Brownstein, S., Liszauer, A., and Jolicoeur, P., 1989, Transgenic mice carrying the mouse mammary tumor virus ras fusion gene: distinct effects in various tissues, Mol. Cell Biol., 9:854–859.PubMedGoogle Scholar
  57. van Zyl, J.A., Menkveld, R., and van Kotze, W., 1975, Oligozoospermia, A seven-year survey of the incidence, chromosomal aberrations, treatment and pregnancy rate, Int. J. Fertil., 20:129–132.PubMedGoogle Scholar
  58. Varmus, H.E., 1984, The molecular genetics of cellular oncogenes, Ann. Rev. Genet., 18:553–612.PubMedCrossRefGoogle Scholar
  59. Yanagimachi, R., Yanagimachi, H., and Rogers, B.J., 1976, The use of zona-free animal ova as a test system for the assessment of the fertilizing capacity of human spermatozoa, Biol. Reprod., 15:471–478.PubMedCrossRefGoogle Scholar
  60. Yanagimachi, R., 1981, Mechanisms of fertilization in mammals, In: “Fertilization and Embryonic Development In Vitro,” Mastroianni Jr., L., and Biggers, J.D., eds., Plenum Publishing Co., New York, 81–182.Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Ramon Mangues
    • 1
  • Irving Seidman
    • 1
  • Angel Pellicer
    • 1
  • Jon W. Gordon
    • 2
  1. 1.Department of Pathology and Kaplan Cancer CenterNew York University Medical CenterNew YorkUSA
  2. 2.Molecular Biology Center, Department of Geriatrics Adult Development and Department of Obstetrics and Gynecology and Reproductive ScienceMount Sinai School of MedicineNew YorkUSA

Personalised recommendations