Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;11(3):370–383. doi: 10.1111/j.1750-3639.2001.tb00406.x

Transgenic and Knockout Mouse Models Clarify Pituitary Development, Function and Disease

Sylvia L Asa 1,✉
PMCID: PMC8098374

Abstract

Mouse models have been used to study various aspects of pituitary development, function and disease. Transgenic or knockout technology has been applied to examine the regulation of hormone gene expression and the pathophysiology of its alterations, to ascertain the factors that determine cell differentiation, and to manipulate oncogenesis. Transgenic mice have elucidated the necessary elements required for the tissue‐ and cell‐specific expression of pituitary hormones. Transgenic and knockout technologies have derived mice with hormone overexpression or abrogation of hormone action, and have identified novel hormones. The role of precursor cells in cell differentiation has been confirmed by genetic ablation of cell lineages. Inactivation of transcription factors implicated in pituitary organogenesis and cytogenesis has proven their critical roles in pituitary development. Pituitary oncogenesis has been studied by promoter‐directed oncogene expression or tumor suppressor gene ablation, by adenohypophysiotropic hormone overexpression, or by growth factor or receptor overexpression. The tumors have provided a number of cell lines for use in the continuing study of pituitary physiology and pathology. These models may also be used in the future to examine novel therapeutic strategies for the management of patients with pituitary disorders.

Full Text

The Full Text of this article is available as a PDF (848.9 KB).

References

  • 1. Alexander JM (2001) Tumor suppressor loss in pituitary tumors. Brain Pathol in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Allen DL, Low MJ, Allen RG, Ben Jonathan N (1995) Identification of two classes of prolactin‐releasing factors in intermediate lobe tumors from transgenic mice. Endocrinology 136: 3093–9. [DOI] [PubMed] [Google Scholar]
  • 3. Asa SL, Kelly MA, Grandy DK, Low MJ (1999) Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia dopamine D2 receptor‐deficient mice. Endocrinology 140: 5348–55. [DOI] [PubMed] [Google Scholar]
  • 4. Asa SL, Kovacs K, Stefaneanu L, Horvath, E , Billestrup, N , Gonzalez‐Manchon, C , Vale, W (1992) Pituitary adenomas in mice transgenic for growth hormone‐releasing hormone. Endocrinology 131: 2083–9. [DOI] [PubMed] [Google Scholar]
  • 4a. Asa SL, Coschigano KT, Bellush L, Kopchick JJ, Ezzat S (2000) Growth hormone (GH) receptor‐deficient mice and GH antagonist‐transgenic mice provide evidence for GH autoregulation in pituitary somatotrophs Am J Pathol 156: 1009–1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Barnhart KM, Mellon PL (1994) The orphan nuclear receptor, steroidogenic factor‐1, regulates the glycoprotein hormone alpha‐subunit gene in pituitary gonadotropes. Mol Endocrinol 8: 878–85. [DOI] [PubMed] [Google Scholar]
  • 6. Bartke A (1999) Role of growth hormone and prolactin in the control of reproduction: what are we learning from transgenic and knock‐out animals Steroids 64: 598–604. [DOI] [PubMed] [Google Scholar]
  • 7. Bartke A, Cecim M, Tang K, Steger RW, Chandrashekar V, Turyn D (1994) Neuroendocrine and reproductive consequences of overexpression of growth hormone in transgenic mice. Proc Soc Exp Biol Med 206: 345–59. [DOI] [PubMed] [Google Scholar]
  • 8. Bartke A, Turyn D, Aguilar CC, Sotelo, AI , Steger, RW , Chen, XZ , Kopchick, JJ (1994) Growth hormone (GH) binding and effects of GH analogs in transgenic mice. Proc Soc Exp Biol Med 206: 190–4. [DOI] [PubMed] [Google Scholar]
  • 9. Batt J, Fladd CA, Asa SL, Rotin D (2001) Neuroendocrine abnormalities in mice lacking the receptor protein tyrosine phosphatase sigma. Mol Endocrinol in press. [DOI] [PubMed] [Google Scholar]
  • 10. Beech J (1981) Pituitary tumors in the horse In: Current Veterinary Therapy, ed. Robinson NE, Philadelphia : W.B. Saunders Co., pp. 164–169. [Google Scholar]
  • 11. Bennani‐Bäiti IM, Asa SL, Song D, Iratni R, Liebhaber SA, Cooke NE (1998) DNase I‐hypersensitive sites I and II of the human growth hormone locus control region are a major developmental activator of somatotrope gene expression. Proc Natl Acad Sci USA 95: 10655–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Borrelli E, Heyman RA, Arias C, Sawchenko PE, Evans RM (1989) Transgenic mice with inducible dwarfism. Nature 339: 538–41. [DOI] [PubMed] [Google Scholar]
  • 13. Borrelli E, Sawchenko PE, Evans RM (1992) Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Natl Acad Sci USA 89: 2764–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Burrows HL, Birkmeier TS, Seasholtz AF, Camper SA (1996) Targeted ablation of cells in the pituitary primordia of transgenic mice. Mol Endocrinol 10: 1467–77. [DOI] [PubMed] [Google Scholar]
  • 15. Burton FH, Hasel KW, Bloom FE, Sutcliffe JG (1991) Pituitary hyperplasia and gigantism in mice caused by a cholera toxin transgene. Nature 350: 74–7. [DOI] [PubMed] [Google Scholar]
  • 16. Cai A, Hayes JD, Patel N, Hyde JF (1999) Targeted over‐expression of galanin in lactotrophs of transgenic mice induces hyperprolactinemia and pituitary hyperplasia. Endocrinology 140: 4955–64. [DOI] [PubMed] [Google Scholar]
  • 17. Chen NY, Chen WY, Striker GE, Kopchick JJ (1997) Co‐expression of bovine growth hormone (GH) and human GH antagonist genes in transgenic mice. Endocrinology 138: 851–4. [DOI] [PubMed] [Google Scholar]
  • 18. Chen WY, White ME, Wagner TE, Kopchick JJ (1991) Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 129: 1402–8. [DOI] [PubMed] [Google Scholar]
  • 19. Chen WY, Wight DC, Wagner TE, Kopchick JJ (1990) Expression of a mutated bovine growth hormone gene suppresses growth of transgenic mice. Proc Natl Acad Sci USA 87: 5061–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Coffin DL, Munson TO (1953) Endocrine diseases of the dog associated with hair loss: sertoli cell tumor of testis, hypothyroidism and canine Cushing's syndrome. J Am Vet Med Assoc 123: 402–8. [PubMed] [Google Scholar]
  • 21. Crabtree JS, Scacheri PC, Ward JM, Garrett‐Beal L, Emmert‐Buck MR, Edgemon KA, Lorang D, Libutti SK, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS (2001) A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 98: 1118–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Cryns VL, Alexander JM, Klibanski A, Arnold A (1993) The retinoblastoma gene in human pituitary tumors. J Clin Endocrinol Metab 77: 644–6. [DOI] [PubMed] [Google Scholar]
  • 23. Elchebly M, Wagner J, Kennedy TE, Lanctôt C, Michaliszyn E, Itié A, Drouin J, Tremblay ML (1999) Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase sigma. Nat Genet 21: 330–3. [DOI] [PubMed] [Google Scholar]
  • 24. Ezzat S (2001) The role of hormones, growth factors and their receptors in pituitary tumorigenesis. Brain Pathol in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Ezzat S, Walpola IA, Ramyar L, Smyth HS, Asa SL (1995) Membrane‐anchored expression of transforming growth factor‐α in human pituitary adenoma cells. J Clin Endocrinol Metab 80: 534–9. [DOI] [PubMed] [Google Scholar]
  • 26. Ezzat S, Zheng L, Zhu X‐F, Wu GE, Asa SL (2001) Pituitary tumorigenesis induced by a novel transforming isoform of fibroblast growth factor receptor 4. Submitted.
  • 27. Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K, Roberts JM (1996) A syndrome of multiorgan hyper‐plasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1‐deficient mice. Cell 85: 733–44. [DOI] [PubMed] [Google Scholar]
  • 28. Franklin DS, Godfrey VL, O'Brien DA, Deng C, Xiong Y (2000) Functional collaboration between different cyclindependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 20: 6147–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Furth J (1969) Pituitary cybernetics and neoplasia. Harvey Lect 63: 47–71. [PubMed] [Google Scholar]
  • 30. Furth J, Nakane P, Pasteels JL (1976) Tumours of the pituitary gland. IARC Sci Publ 201–37. [PubMed]
  • 31. Hammer GD, Fairchild‐Huntress V, Low MJ (1990) Pituitary‐specific and hormonally regulated gene expression directed by the rat proopiomelanocortin promoter in transgenic mice. Mol Endocrinol 4: 1689–97. [DOI] [PubMed] [Google Scholar]
  • 32. Hayashi Y, Xie J, Weiss RE, Pohlenz J, Refetoff S (1998) Selective pituitary resistance to thyroid hormone produced by expression of a mutant thyroid hormone receptor beta gene in the pituitary gland of transgenic mice. Biochem Biophys Res Commun 245: 204–10. [DOI] [PubMed] [Google Scholar]
  • 33. Helseth A, Siegal GP, Haug E, Bautch VL (1992) Transgenic mice that develop pituitary tumors. A model for Cushing's disease. Am J Pathol 140: 1071–80. [PMC free article] [PubMed] [Google Scholar]
  • 34. Horn F, Windle JJ, Barnhart KM, Mellon PL (1992) Tissue‐specific gene expression in the pituitary: the glycoprotein hormone alpha‐subunit gene is regulated by a gonadotrope‐specific protein. Mol Cell Biol 12: 2143–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Hu N, Gutsmann A, Herbert DC, Bradley A, Lee W‐H, Lee EY (1994) Heterozygous Rb‐1delta/+ mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9: 1021–7. [PubMed] [Google Scholar]
  • 36. Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL (1994) The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 8: 2302–12. [DOI] [PubMed] [Google Scholar]
  • 37. Ishibashi M, Yamaji T, Takaku F, Teramoto A, Fukushima T, Toyama M, Kamoi K (1987) Effect of GnRH‐associated peptide on prolactin secretion from human lactotrope adenoma cells in culture. Acta Endocrinol (Copenh) 116: 81–4. [DOI] [PubMed] [Google Scholar]
  • 38. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA (1992) Effects of an Rb mutation in the mouse. Nature 359: 295–300. [DOI] [PubMed] [Google Scholar]
  • 39. Jones BK, Monks BR, Liebhaber SA, Cooke NE (1995) The human growth hormone gene is regulated by a multicomponent locus control region. Mol Cell Biol 15: 7010–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben‐Jonathan N, Grandy DK, Low MJ (1997) Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor‐deficient mice. Neuron 19: 103–13. [DOI] [PubMed] [Google Scholar]
  • 41. Kelly PA, Binart N, Lucas B, Bouchard B, Goffin V (2001) Implications of multiple phenotypes observed in prolactin receptor knockout mice. Front Neuroendocrinol 22: 140–5. [DOI] [PubMed] [Google Scholar]
  • 42. Kendall SK, Saunders TL, Jin L, Lloyd RV, Glode LM, Nett TM, Keri RA, Nilson JH, Camper SA (1991) Targeted ablation of pituitary gonadotropes in transgenic mice. Mol Endocrinol 5: 2025–36. [DOI] [PubMed] [Google Scholar]
  • 43. Kiaer W, Norgaard JOR (1969) Granulomatous hypophysitis and thyroiditis with lymphocytic adrenalitis. Acta Pathol Microbiol Scand 76: 229–38. [PubMed] [Google Scholar]
  • 44. Kiyokawa H, Kineman RD, Manova‐Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A (1996) Enhanced growth of mice lacking the cyclin‐dependent kinase inhibitor function of p27Kip1 . Cell 85: 721–32. [DOI] [PubMed] [Google Scholar]
  • 45. Kumar TR, Fairchild‐Huntress V, Low MJ (1992) Gonadotrope‐specific expression of the human folliclestimulating hormone beta‐subunit gene in pituitaries of transgenic mice. Mol Endocrinol 6: 81–90. [DOI] [PubMed] [Google Scholar]
  • 46. Kumar TR, Graham KE, Asa SL, Low MJ (1998) Simian virus 40 T antigen‐induced gonadotroph adenomas: A model of human null cell adenomas. Endocrinology 139: 3342–51. [DOI] [PubMed] [Google Scholar]
  • 47. Lew D, Brady H, Klausing K, Yaginuma K, Theill LE, Stauber C, Karin M, Mellon PL (1993) GHF‐1‐promoter‐targeted immortalization of a somatotropic progenitor cell results in dwarfism in transgenic mice. Genes Dev 7: 683–93. [DOI] [PubMed] [Google Scholar]
  • 48. Liebelt AG (1979) Tumours of the pituitary gland. IARC Sci Publ 23: 411–50. [PubMed] [Google Scholar]
  • 49. Liebhaber SA, Urbanek M, Ray J, Tuan RS, Cooke NE (1989) Characterization and histologic localization of human growth hormone‐ variant gene expression in the placenta. J Clin Invest 83: 1985–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Liu B, Hammer GD, Rubinstein M, Mortrud M, Low MJ (1992) Identification of DNA elements cooperatively activating proopiomelanocortin gene expression in the pituitary glands of transgenic mice. Mol Cell Biol 12: 3978–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Lloyd RV, Jin L, Chang A, Kulig E, Camper SA, Ross BD, Downs TR, Frohman LA (1992) Morphologic effects of hGRH gene expression on the pituitary, liver, and pancreas of MT‐hGRH transgenic mice. An in situ hybridization analysis. Am J Pathol 141: 895–906. [PMC free article] [PubMed] [Google Scholar]
  • 52. Low MJ, Liu B, Hammer GD, Rubinstein M, Allen RG (1993) Post‐translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC‐simian virus 40 large T antigen transgene. J Bio Chem 268: 24967–75. [PubMed] [Google Scholar]
  • 53. Lyons J, Landis CA, Harsh G, Vallar L, Grünewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR, et al. (1990) Two G protein oncogenes in human endocrine tumors. Science 249: 655–9. [DOI] [PubMed] [Google Scholar]
  • 54. Markkula M, Kananen K, Paukku T, Männistö A, Loune E, Fröjdman K, Pelliniemi LJ, Huhtaniemi I (1995) Induced ablation of gonadotropins in transgenic mice expressing herpes simplex virus thymidine kinase under the FSH beta‐subunit promoter. Mol Cell Endocrinol 108: 1–9. [DOI] [PubMed] [Google Scholar]
  • 55. Markkula MA, Hamalainen TM, Zhang F, Kim KE, Maurer RA, Huhtaniemi IT (1993) The FSH beta‐subunit promoter directs the expression of Herpes simplex virus type 1 thymidine kinase to the testis of transgenic mice. Mol Cell Endocrinol 96: 25–36. [DOI] [PubMed] [Google Scholar]
  • 56. McAndrew J, Paterson AJ, Asa SL, McCarthy KJ, Kudlow JE (1995) Targeting of transforming growth factor‐α expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas. Endocrinology 136: 4479–88. [DOI] [PubMed] [Google Scholar]
  • 57. Murphy D, Bishop A, Rindi G et al. (1987) Mice transgenic for a vasopressin‐SV40 hybrid oncogene develop tumors of the endocrine pancreas and the anterior pituitary: A possible model for human multiple endocrine neoplasia type 1. Am J Pathol 129: 552–66. [PMC free article] [PubMed] [Google Scholar]
  • 58. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama K (1996) Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85: 707–20. [DOI] [PubMed] [Google Scholar]
  • 59. 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: 613–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Palmiter RD, Norstedt G, Gelinas RE, Hammer RE, Brinster RL (1983) Metallothionein‐human GH fusion genes stimulate growth of mice. Science 222: 809–14. [DOI] [PubMed] [Google Scholar]
  • 61. Pei L, Melmed S, Scheithauer B, Kovacs K, Benedict WF, Prager D (1995) Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors: Evidence for a chromosome 13 tumor suppressor gene other than RB . Cancer Res 55: 1613–6. [PubMed] [Google Scholar]
  • 62. Rubinstein M, Mortrud M, Liu B, Low MJ (1993) Rat and mouse proopiomelanocortin gene sequences target tissue‐specific expression to the pituitary gland but not to the hypothalamus of transgenic mice. Neuroendocrinology 58: 373–80. [DOI] [PubMed] [Google Scholar]
  • 63. Schlumberger HG (1956) Neoplasia in the parakeet. II. Transplantation of the pituitary tumor. Cancer Res 16: 149–53. [PubMed] [Google Scholar]
  • 64. Sheng HZ, Moriyama K, Yamashita T, Li H, Potter SS, Mahon KA, Westphal H (1997) Multistep control of pituitary organogenesis. Science 278: 1809–12. [DOI] [PubMed] [Google Scholar]
  • 65. Shewchuk BM, Asa SL, Cooke NE, Liebhaber SA (1999) Pit‐1 binding sites at the somatotrope‐specific DNase I hypersensitive sites I, II of the human growth hormone locus control region are essential for in vivo hGH‐N gene activation. J Biol Chem 274: 35725–33. [DOI] [PubMed] [Google Scholar]
  • 66. Spada A, Vallar L, Faglia G (1992) G protein oncogenes in pituitary tumors. Trends Endocrinol Metab 3: 355–60. [DOI] [PubMed] [Google Scholar]
  • 67. Stenzel‐Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W (1992) Development of Cushing's syndrome in corticotropin‐releasing factor transgenic mice. Endocrinology 130: 3378–86. [DOI] [PubMed] [Google Scholar]
  • 68. Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR (1991) Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non‐phosphorylatable CREB mutant. Nature 350: 622–4. [DOI] [PubMed] [Google Scholar]
  • 69. Ueda G, Takizawa S, Moy P, Marolla F, Furth J (1968) Characterization of four transplantable mammotropic pituitary tumor variants in the rat. Cancer Res 28: 1963–75. [PubMed] [Google Scholar]
  • 70. Wallace MJ, Batt J, Fladd CA, Henderson JT, Skarnes W, Rotin D (1999) Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma. Nat Genet 21: 334–8. [DOI] [PubMed] [Google Scholar]
  • 71. Yu R, Melmed S (2001) Oncogene acivation in pituitary tumors. Brain Pathol, in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Zhou Y, Xu BC, Maheshwari HG, He L, Reed M, Lozykowski M, Okada S, Cataldo L, Coschigamo K, Wagner TE, Baumann G, Kopchick JJ (1997) A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA 94: 13215–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Zhu J, Leon SP, Beggs AH, Busque L, Gilliland DG, Black PM (1994) Human pituitary adenomas show no loss of heterozygosity at the retinoblastoma gene locus. J Clin Endocrinol Metab 78: 922–7. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES