, Volume 26, Issue 3, pp 227–233 | Cite as

Gonadotropin gene targeting and biological implications

  • T. Rajendra Kumar


Pituitary gonadotropins FSH and LH are heterodimeric glycoproteins consisting of a common alpha and a hormone-specific beta subunit that are non-covalently linked. These hormones orchestrate gonadal growth, differentiation, and function by regulating both steroidogenesis and gametogenesis. Advances in the past two decades in manipulating the mouse genome by site-specific mutagenesis have heralded a new dimension to our understanding of the biology of gonadotropins. Using these gene-targeting approaches, knockout mice lacking the hormone-specific gonadotropin subunits, and hence the functional dimeric hormones, have been generated. These individual gonadotropin-deficient mice are useful to delineate the distinct in vivo biological roles of FSH and LH. These mice also serve as valuable genetic tools to study the signaling mechanisms within the gonads and help a better understanding of some forms of human infertility.

Key Words

Knockout mice pituitary LH FSH hCG testis ovary 


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  1. 1.
    Pierce, J. G. and Parsons, T. F. (1981). Annu. Rev. Biochem. 50, 465–495.PubMedCrossRefGoogle Scholar
  2. 2.
    Bousfield, G. R., Perry, W. M., and Ward, D. N. (1994). In: The physiology of reproduction. Knobil, E. and Neill, J. D. (eds.). Raven Press: New York, pp. 1749–1792.Google Scholar
  3. 3.
    Ruf, F., Fink, M. Y., and Sealfon, S. C. (2003). Front. Neuroendocrinol. 24, 181–199.PubMedCrossRefGoogle Scholar
  4. 4.
    Shimasaki, S., Moore, R. K., Otsuka, F., and Erickson, G. F. (2004). Endocr. Rev. 25, 72–101.PubMedCrossRefGoogle Scholar
  5. 5.
    Bradley, A., Ramirez-Solis, R., Zheng, H., Hasty, P., and Davis, A. (1992). Ciba Found Symp. 165, 256–269; discussion 269–276.PubMedGoogle Scholar
  6. 6.
    Bradley, A., Hasty, P., Davis, A., and Ramirez-Solis, R. (1992). Biotechnology (NY) 10, 534–539.CrossRefGoogle Scholar
  7. 7.
    Bradley, A. (1993). Recent Prog. Horm. Res. 48, 237–251.PubMedGoogle Scholar
  8. 8.
    Ramirez-Solis, R. and Bradley, A. (1994). Curr. Opin. Biotechnol. 5, 528–533.PubMedCrossRefGoogle Scholar
  9. 9.
    Justice, M. J., Zheng, B., Woychik, R. P., and Bradley, A. (1997). Methods 13, 423–436.PubMedCrossRefGoogle Scholar
  10. 10.
    Bradley, A., Zheng, B., and Liu, P. (1998). Int. J. Dev. Biol. 42, 943–950.PubMedGoogle Scholar
  11. 11.
    Mills, A. A. and Bradley, A. (2001). Trends Genet. 17, 331–339.PubMedCrossRefGoogle Scholar
  12. 12.
    Yu, Y. and Bradley, A. (2001). Nat. Rev. Genet. 2, 780–790.PubMedCrossRefGoogle Scholar
  13. 13.
    van der Weyden, L., Adams, D. J., and Bradley, A. (2002). Physiol. Genomics 11, 133–164.PubMedGoogle Scholar
  14. 14.
    Capecchi, M. R. (1989). Science 244, 1288–1292.PubMedCrossRefGoogle Scholar
  15. 15.
    Capecchi, M. R. (1989). Trends Genet. 5, 70–76.PubMedCrossRefGoogle Scholar
  16. 16.
    Kendall, S. K., Samuelson, L. C., Saunders, T. L., Wood, R. I., and Camper, S. A. (1995). Genes Dev. 9, 2007–2019.PubMedGoogle Scholar
  17. 17.
    Mason, A. J., Hayflick, J. S., Zoeller, R. T., et al. (1986). Science 234, 1366–1371.PubMedCrossRefGoogle Scholar
  18. 18.
    Mason, A. J., Pitts, S. L., Nikolics, K., et al. (1986). Science 234, 1372–1378.PubMedCrossRefGoogle Scholar
  19. 19.
    Mason, A. J., Pitts, S. L., Nikolics, K., et al. (1987). Ann. NY Acad. Sci. 513, 16–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Kumar, T. R., Wang, Y., Lu, N., and Matzuk, M. M. (1997). Nat. Genet. 15, 201–204.PubMedCrossRefGoogle Scholar
  21. 21.
    Wreford, N. G., Kumar, T. R., Matzuk, M. M., and de Kretser, D. M. (2001). Endocrinology 142, 2916–2920.PubMedCrossRefGoogle Scholar
  22. 22.
    Kumar, T. R., Varani, S., Wreford, N. G., Telfer, N. M., de Kretser, D. M., and Matzuk, M. M. (2001). Endocrinology 142, 3512–3518.PubMedCrossRefGoogle Scholar
  23. 23.
    Baker, P. J., Pakarinen, P., Huhtaniemi, I. T., et al. (2003). Endocrinology 144, 138–145.PubMedCrossRefGoogle Scholar
  24. 24.
    McLachlan, R. I., O’Donnell, L., Meachem, S. J., et al. (2002). Recent Prog. Horm. Res. 57, 149–179.PubMedCrossRefGoogle Scholar
  25. 25.
    McLachlan, R. I., O’Donnell, L., Meachem, S. J., et al. (2002). J. Androl. 23, 149–162.PubMedGoogle Scholar
  26. 26.
    Moudgal, N. R., Jeyakumar, M., Krishnamurthy, H. N., Sridhar, S., Krishnamurthy, H., and Martin, F. (1997). Hum. Reprod. Update 3, 335–346.PubMedCrossRefGoogle Scholar
  27. 27.
    Moudgal, N. R. and Sairam, M. R. (1998). Hum. Reprod. 13, 916–919.PubMedCrossRefGoogle Scholar
  28. 28.
    Plant, T. M. and Marshall, G. R. (2001). Endocr. Rev. 22, 764–786.PubMedCrossRefGoogle Scholar
  29. 29.
    Furth, P. A., St Onge, L., Boger, H., et al. (1994). Proc. Natl. Acad. Sci. USA 91, 9302–9306.PubMedCrossRefGoogle Scholar
  30. 30.
    Gossen, M. and Bujard, H. (2002). Annu. Rev. Genet. 36, 153–173.PubMedCrossRefGoogle Scholar
  31. 31.
    Schonig, K., Schwenk, F., Rajewsky, K., and Bujard, H. (2002). Nucleic Acids Res. 30, e134.Google Scholar
  32. 32.
    Burns, K. H., Yan, C., Kumar, T. R., and Matzuk, M. M. (2001). Endocrinology 142, 2742–2751.PubMedCrossRefGoogle Scholar
  33. 33.
    Combelles, C. M., Carabatsos, M. J., Kumar, T. R., Matzuk, M. M., and Albertini, D. F. (2004). Mol. Reprod. Dev. 69, 347–355.PubMedCrossRefGoogle Scholar
  34. 34.
    Abel, M. H., Huhtaniemi, I., Pakarinen, P., Kumar, T. R., and Charlton, H. M. (2003). Reproduction 125, 165–173.PubMedCrossRefGoogle Scholar
  35. 35.
    Kumar, T. R., Low, M. J., and Matzuk, M. M. (1998). Endocrinology 139, 3289–3295.PubMedCrossRefGoogle Scholar
  36. 36.
    Matzuk, M. M., Finegold, M. J., Su, J. G., Hsueh, A. J., and Bradley, A. (1992). Nature 360, 313–319.PubMedCrossRefGoogle Scholar
  37. 37.
    Matzuk, M. M., Finegold, M. J., Mather, J. P., Krummen, L., Lu, H., and Bradley, A. (1994). Proc. Natl. Acad. Sci. USA 91, 8817–8821.PubMedCrossRefGoogle Scholar
  38. 38.
    Kumar, T. R., Wang, Y., and Matzuk, M. M. (1996). Endocrinology 137, 4210–4216.PubMedCrossRefGoogle Scholar
  39. 39.
    Kumar, T. R., Palapattu, G., Wang, P., et al. (1999). Mol. Endocrinol. 13, 851–865.PubMedCrossRefGoogle Scholar
  40. 40.
    Bilezikjian, L. M., Blount, A. L., Corrigan, A. Z., Leal, A., Chen, Y., and Vale, W. W. (2001). Clin. Exp. Pharmacol. Physiol. 28, 244–248.PubMedCrossRefGoogle Scholar
  41. 41.
    Woodruff, T. K. (1998). Biochem. Pharmacol. 55, 953–963.PubMedCrossRefGoogle Scholar
  42. 42.
    Pangas, S. A. and Woodruff, T. K. (2000). Trends Endocrinol. Metab. 11, 309–314.PubMedCrossRefGoogle Scholar
  43. 43.
    Gaddy-Kurten, D., Tsuchida, K., and Vale, W. (1995). Recent Prog. Horm. Res. 50, 109–129.PubMedGoogle Scholar
  44. 44.
    Roberts, V. J., Peto, C. A., Vale, W., and Sawchenko, P. E. (1992). Neuroendocrinology 56, 214–224.PubMedGoogle Scholar
  45. 45.
    Cameron, V. A., Nishimura, E., Mathews, L. S., Lewis, K. A., Sawchenko, P. E., and Vale, W. W. (1994). Endocrinology 134, 799–808.PubMedCrossRefGoogle Scholar
  46. 46.
    Matzuk, M. M., Kumar, T. R., and Bradley, A. (1995). Nature 374, 356–360.PubMedCrossRefGoogle Scholar
  47. 47.
    Kumar, T. R., Agno, J., Janovick, J. A., Conn, P. M., and Matzuk, M. M. (2003). Mol. Cell. Endocrinol. 212, 19–27.PubMedCrossRefGoogle Scholar
  48. 48.
    Coerver, K. A., Woodruff, T. K., Finegold, M. J., Mather, J., Bradley, A., and Matzuk, M. M. (1996). Mol. Endocrinol. 10, 534–543.PubMedCrossRefGoogle Scholar
  49. 49.
    Josso, N. and Rey, R. (1996). Curr. Opin. Pediatr. 8, 396–400.PubMedCrossRefGoogle Scholar
  50. 50.
    Josso, N. and di Clemente, N. (1997). Curr. Opin. Genet. Dev. 7, 371–377.PubMedCrossRefGoogle Scholar
  51. 51.
    Josso, N., Racine, C., di Clemente, N., Rey, R., and Xavier, F. (1998). Mol. Cell. Endocrinol. 145, 3–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Josso, N., di Clemente, N., and Gouedard, L. (2001). Mol. Cell. Endocrinol. 179, 25–32.PubMedCrossRefGoogle Scholar
  53. 53.
    Josso, N. and di Clemente, N. (2003). Trends Endocrinol. Metab. 14, 91–97.PubMedCrossRefGoogle Scholar
  54. 54.
    Durlinger, A. L., Gruijters, M. J., Kramer, P., et al. (2001). Endocrinology 142, 4891–4899.PubMedCrossRefGoogle Scholar
  55. 55.
    Ma, X., Dong, Y. L., Matzuk, M. M., Yashwanth, R., and Kumar, T. R. (2004). Proc. Natl. Acad. Sci. USA 101, 17294–17299.PubMedCrossRefGoogle Scholar
  56. 56.
    Lei, Z. M., Mishra, S., Zou, W., et al. (2001). Mol. Endocrinol. 15, 184–200.PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang, F. P., Poutanen, M., Wilbertz, J., and Huhtaniemi, I. (2001). Mol. Endocrinol. 15, 172–183.PubMedCrossRefGoogle Scholar
  58. 58.
    Chang, C., Chen, Y. T., Yeh, S. D., et al. (2004). Proc. Natl. Acad. Sci. USA 101, 6876–6881.PubMedCrossRefGoogle Scholar
  59. 59.
    De Gendt, K., Swinnen, J. V., Saunders, P. T., et al. (2004). Proc. Natl. Acad. Sci. USA 101, 1327–1332.PubMedCrossRefGoogle Scholar
  60. 60.
    Holdcraft, R. W. and Braun, R. E. (2004). Development 131, 459–467.PubMedCrossRefGoogle Scholar
  61. 61.
    Markkula, M. and Huhtaniemi, I. (1996). Rev. Reprod. 1, 97–106.PubMedCrossRefGoogle Scholar
  62. 62.
    Kumar, T. R. and Matzuk, M. M. (2000). In: Gene engineering and molecular models in endocrinology. Shupnik, M. A. (ed.). The Humana Press: Totowa, NJ, 2000.Google Scholar
  63. 63.
    Huhtaniemi, I. (2000). J. Reprod. Fertil. 119, 173–186.PubMedCrossRefGoogle Scholar
  64. 64.
    Aittomaki, K., Lucena, J. L., Pakarinen, P., et al. (1995). Cell 82, 959–968.PubMedCrossRefGoogle Scholar
  65. 65.
    Aittomaki, K., Herva, R., Stenman, U. H., et al. (1996). J. Clin. Endocrinol. Metab. 81, 3722–3726.PubMedCrossRefGoogle Scholar
  66. 66.
    Tapanainen, J. S., Aittomaki, K., Min, J., Vaskivuo, T., and Huhtaniemi, I. T. (1997). Nat. Genet. 15, 205–206.PubMedCrossRefGoogle Scholar
  67. 67.
    Matthews, C. H., Borgato, S., Beck-Peccoz, P., et al. (1993). Nat. Genet. 5, 83–86.PubMedCrossRefGoogle Scholar
  68. 68.
    Huhtaniemi, I. T. (2002). Best Pract. Res. Clin. Endocrinol. Metab. 16, 123–138.PubMedCrossRefGoogle Scholar
  69. 69.
    Huhtaniemi, I., Jiang, M., Nilsson, C., and Pettersson, K. (1999). Mol. Cell. Endocrinol. 151, 89–94.PubMedCrossRefGoogle Scholar
  70. 70.
    Weiss, J., Axelrod, L., Whitcomb, R. W., Harris, P. E., Crowley, W. F., and Jameson, J. L. (1992). N. Engl. J. Med. 326, 179–183.PubMedCrossRefGoogle Scholar
  71. 71.
    Kumar, T. R. (2001). In: Transgenics in endocrinology. Matzuk, M. M., Brown, C. E., and Kumar, T. R. (ed.). Humana Press: Totowa, pp. 425–466.Google Scholar
  72. 72.
    Mellon, P. L., Windle, J. J., and Weiner, R. I. (1991). Recent Prog. Horm. Res. 47, 69–93; discussion 93–66.PubMedGoogle Scholar
  73. 73.
    Garcia-Campayo, V., Kumar, T. R., and Boime, I. (2002). Endocrinology 143, 3773–3778.PubMedCrossRefGoogle Scholar
  74. 74.
    Garcia-Campayo, V., Boime, I., Ma, X., Daphna-Iken, D., and Kumar, T. R. (2005). Biol. Reprod. 72, 301–308.PubMedCrossRefGoogle Scholar
  75. 75.
    Narayan, P., Meehan, T. P., and Puett, D. (2003). Biol. Reprod. 68(Suppl. 1), 312–313.Google Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas City
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas City

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