Molecular and Cellular Ontogeny of Distinct Pituitary Cell Types

  • Cheryl A. Pickeet
  • Authur Gutierrez-Hartmann
Part of the Contemporary Endocrinology book series (COE, volume 3)


The development of the anterior pituitary gland has been studied extensively over several decades. With its five distinct cell types, the anterior pituitary provides a model system for investigations of the mechanisms involved in cellular commitment and tissue-specific gene expression. In recent years these studies have begun to yield fascinating information that will be valuable to our general understanding of the molecular interactions that take place during differentiation. In this chapter, we will review the current state of knowledge concerning the role of trophic/growth factors and hormones, the nuclear transcription factors, and the genetic elements required for normal development of the five distinct cell types of the anterior pituitary. We will also discuss the molecular basis of abnormal differentiation/development of the human pituitary and the potential role that aberrancy of these mechanisms may play in certain pituitary disorders. This is a broad topic, and we cannot do justice to all the many invaluable studies that have contributed to our understanding of pituitary development; instead we will concentrate on those areas in which our knowledge is most complete.


Growth Hormone Pituitary Adenoma Anterior Pituitary Pituitary Cell Dwarf Mouse 
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  1. 1.
    Dearden NM, Holmes RL. Cyto-differentiation and portal vascular development in the mouse adenohy-pophysis. J Anat 1976; 121:551–569.PubMedGoogle Scholar
  2. 2.
    Kaufman MH. The Atlas of Mouse Development. Academic, London, 1992.Google Scholar
  3. 3.
    Rugh R. The Mouse: Its Reproduction and Development. Burgess Publishing, Minneapolis, MN, 1968.Google Scholar
  4. 4.
    Watanabe YG, Daikoku S. An immunohistochemical study on the cytogenesis of adenohypophysial cells in fetal rats. Dev Biol 1979; 68:557–567.PubMedGoogle Scholar
  5. 5.
    Ikeda H, Suzuki J, Sasano N, Niizuma H. The development and morphogenesis of the human pituitary gland. Anat Embryol 1988; 178:327–336.PubMedGoogle Scholar
  6. 6.
    Schechter JE, Pattison A, Pattison T. Development of the vasculature of the anterior pituitary: ontogeny of basic fibroblast growth factor. Developmental Dynamics 1993; 197:81–93.PubMedGoogle Scholar
  7. 7.
    Borrelli E. Pitfalls during development: controlling differentiation of the pituitary gland. Trends Genetics 1994; 10:222–224.Google Scholar
  8. 8.
    Karin M, Castrillo J-L, Theill LE. Growth hormone gene regulation: a paradigm for cell type-specific gene activation. Trends Genetics 1990; 6:92–96.Google Scholar
  9. 9.
    Voss JW, Rosenfeld MG. Anterior pituitary development: short tales from dwarf mice. Cell 1990; 70:527–530.Google Scholar
  10. 10.
    Theill LE, Karin M. Transcriptional control of GH expression and anterior pituitary development. Endocrine Rev 1993; 14:670–689.Google Scholar
  11. 11.
    Coates PJ, Doniach I. Development of folliculo-stellate cells in the human pituitary. Acta Endocrinologica 1988; 119:16–20.PubMedGoogle Scholar
  12. 12.
    Simmons DM, Voss JW, Ingraham HA, Holloway JM, Broide RS, Rosenfeld MG, Swanson LW. Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev 1990; 4:695–711.PubMedGoogle Scholar
  13. 13.
    Asa SL, Kovacs K, Lazlo FA, Domokos I, Ezrin C. Human fetal adenohypophysis: histologic and im-munocytochemical analysis. Neuroendocrinology 1986; 43:308–316.PubMedGoogle Scholar
  14. 14.
    Asa SL, Kovacs K, Singer W. Human fetal adenohypophysis: morphologic and functional analysis in vitro. Neuroendocrinology 1991; 53:562–572.PubMedGoogle Scholar
  15. 15.
    Barinaga M, Yamnamoto G. Rivier C, Vale W, Evans R, Rosenfeld MG. Transcriptional regulation of growth hormone gene expression by growth hormone-releasing factor. Nature 1983; 306:84–85.PubMedGoogle Scholar
  16. 16.
    Gick GG, Zeytin F, Brazeau P, Ling NC, Esch F, Bancroft FC. Growth hormone releasing factor regulates growth hormone mRNA in primary cultures of rat pituitary cells. Proc Natl Acad Sci USA 1984; 81:1553–1555.PubMedGoogle Scholar
  17. 17.
    Zeytin FN, Gick GG, Brazeau P, Ling N, McLaughlin M, Bancroft C. Growth hormone (GH)-releasing factor does not regulate GH release or GH mRNA levels in GH3 cells. Endocrinology 1984; 114:2054–2059.PubMedGoogle Scholar
  18. 18.
    Asa SL, Kovacs K, Stefaneanu L, Horvath E, Billestrup N, Gonzales-Manchon C, Vale W. Pituitary mam-mosomatotroph adenomas develop in old mice transgenic for growth hormone releasing hormone. Proc Soc Exp Biol Med 1990; 193:232–235.PubMedGoogle Scholar
  19. 19.
    Lloyd RV, Jin L, Chang A, Kulig E, Camper SA, Ross BD, Downs TR, Frohman LA. Morphologic effects of hGRH gene expression on the pituitary, liver, and pancreas of MT-hGRH transgenic mice. Amer J Pathol 1992; 141:895–906.Google Scholar
  20. 20.
    Mayo KE, Hammer RE, Swanson LW, Brinster RL, Rosenfeld MG, Evans RM. Dramatic pituitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene. Mol Endocrinol 1988; 2:606–612.PubMedGoogle Scholar
  21. 21.
    Stefaneanu L, Kovacs K, Horvath E, Asa SL, Losinski NE, Billestrup N. Price J. Vale W. Adenohy-pophysial changes in mice transgenic for human growth hormone-releasing factor (hGRF): A histological, immunocytochenlical and electron microscopic investigation. Endocrinology 1989; 125:2710–2718.PubMedGoogle Scholar
  22. 22.
    Cheng TC, Beamer WG, Phillips JA, Bartke A, Mallonee RL, Dowling C. Etiology of growth hormone deficiency in Little, Ames and Snell dwarf mice. Endocrinology 1983; 113:1669–1678.PubMedGoogle Scholar
  23. 23.
    Lin S-C, Lin CR, Gukovsky I, Lusis AJ, Sawchenko PE, Rosenfeld MG. Molecular basis of the little mouse phenotype and implications for cell type-specific growth. Nature 1993; 364:208–213.PubMedGoogle Scholar
  24. 24.
    Buckwalter MS, Katz RW, Camper SA. Localization of the panhypopituitary dwarf mutation (df) on mouse chromosome 11 in intersubspecific backcross. Genomics 1991; 10:515–526.PubMedGoogle Scholar
  25. 25.
    Slabaugh MB, Lieberman ME, Rutledge JJ, Gorski J. Ontogeny of growth hormone and prolactin gene expression in mice. Endocrinology 1982; 110:1489–1497.PubMedGoogle Scholar
  26. 26.
    O’Hara BF, Bendotti D, Reeves RH, Oster-Granite MI, Coyle JT, Gearhart JD. Genetic mapping and analysis of somatostatin expression in Snell dwarf mice. Mol Brain Res 1988; 4:283–292.Google Scholar
  27. 27.
    Gage PJ, Lossie AC, Scarlett LM, Lloyd RV, Camper SA. Ames dwarf mice exhibit somatotrope commitment but lack growth hormone-releasing factor response. Endocrinology 1995; 136:1161–1167.PubMedGoogle Scholar
  28. 28.
    Lin C, Lin S-C, Chang C-P, Rosenfeld MG. Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth. Nature 1992; 360:765–768.PubMedGoogle Scholar
  29. 29.
    Camper SA, Saunders TL, Katz RW, Reeves RH. The Pit-1 transcription factor gene is a candidate for the Snell dwarf mutation. Genomics 1990; 8:586–590.PubMedGoogle Scholar
  30. 30.
    Li S, Crenshaw EB, Rawson EJ, Simmons DM, Swanson LW, Rosenfeld MG. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU domain gene pit-1. Nature 1990; 347:528–533.PubMedGoogle Scholar
  31. 31.
    Gertz BJ, Contreras LH, McComb KI, Kivacs JB, Tyrrel JB, Dallman MG. Chronic administration of corticotropin-releasing factor increases pituitary corticotroph number. Endocrinology 1987; 120:381–388.PubMedGoogle Scholar
  32. 32.
    Childs GV, Rougeau D, Unabia G. Corticotropin-releasing hormone and epidermal growth factor: Mitogens for anterior pituitary corticotropes. Endocrinology 1995; 136:1595–1602.PubMedGoogle Scholar
  33. 33.
    Asa SL, Kovacs K, Hammer GD, Liu B, Roow BA, Low MJ. Pituitary corticotroph hyperplasia in rats implanted with a medullary thyroid carcinoma cell line transfected with a corticotropin-releasing hormone complementary deoxyribonucleic acid expression vector. Endocrinology 1992; 131:715–720.PubMedGoogle Scholar
  34. 34.
    Hotta M, Shibasaki T, Masuda A, Imaki T, Demura H, Olmo H, Daikoku S, Benoit R, Ling N, Shizume K. Ontogeny of pituitary responsiveness to corticotropin-releasing hormone in rat. Regulatory Peptides 1988; 21:245–252.PubMedGoogle Scholar
  35. 35.
    Dalkin AC, Haisenleder DJ, Ortolano GA, Ellis TR, Marshall JC. The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology 1989; 125:917–922.PubMedGoogle Scholar
  36. 36.
    Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular biology of the pituitary gonadotropins. Endocrine Reviews 1990; 11:177–199.PubMedGoogle Scholar
  37. 37.
    Murakami M, Muri M, Kato Y. Kobayashi I. Hypothalamic thyrotropin-releasing hormone regulates pituitary beta- and alpha-subunit mRNA levels in the rat. Neuroendocrinology 1991; 53:276–280.PubMedGoogle Scholar
  38. 38.
    Shupnik MA, Greenspan SL, Ridgway EC. Transcriptional regulation of thyrotropin subunit genes by thyrotropin-releasing hormone and dopamine in pituitary cell culture. J Biol Chem. 1986; 261:12,675–12,679.Google Scholar
  39. 39.
    Tashjian AH, Jr., Barowsky NJ, Jensen DK. Thyroptropin-releasing hormone: Direct evidence for stimula tion of prolactin production by pituitary cells in culture. Biochem Biohys Res Commun 1971; 43:516–523.Google Scholar
  40. 40.
    Ramsdell JS. Thyrotropin-releasing hormone inhibits GH4 pituitary cell proliferation by blocking entry into S phase. Endocrinology 1990; 126:472–479.PubMedGoogle Scholar
  41. 41.
    Hyyppa M. Hypothalamic monamines in human fetuses. Neuroendocrinology 1972; 9:257–266.PubMedGoogle Scholar
  42. 42.
    Patel YC, Srikant CB. Somatostatin mediation of adenohypophysial secretion. Annual Rev Physiol 1986; 48:551–567.PubMedGoogle Scholar
  43. 43.
    Lamberts S, Krening E, Reubi J-C. The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocrine Rev. 1991; 12:450–482.Google Scholar
  44. 44.
    Bruno J-F, Xu Y, Song J, Berelowitz M. Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 1993; 133:2561–2567.PubMedGoogle Scholar
  45. 45.
    Wulfsen I, Meyerhorf W, Fehr S, Richter D. Expression patterns of rat somatostatin receptor genes in pre-and postnatal brain and pituitary. J Neurochem 1993; 61:1549–1552.PubMedGoogle Scholar
  46. 46.
    Srkalovic G, Cai R-Z, Schally AV. Evaluation of receptors for somatostatin in various tumour tissues using different analogues. J Clin Endocrinol Metab 1990; 70:661–669.PubMedGoogle Scholar
  47. 47.
    Reubi JC, Heitz PU, Landolt AM. Visualization of somatostatin receptors and correlation with immuno-reactive growth hormone and prolactin in human pituitary adenomas. Evidence for different tumour subclasses. J Clin Endocrinol Metab 1987; 65:65–73.PubMedGoogle Scholar
  48. 48.
    Katznelson L, Oppenheim DS, Coughlin JF, Kliman B. Scheinfeld DA, Klibanski A. Chronic somatostatin analogue administration in patients with α-subunit secreting pituitary tumors. J Clin Endocrinol Metab 1992;75:1318–1325.PubMedGoogle Scholar
  49. 49.
    Massague J. The TGF-beta family of growth and differentiation factors. Cell 1987; 49:437–438.PubMedGoogle Scholar
  50. 50.
    Katayama T, Shioto K, Takahashi M. Activin A increases the number of follicle stimulating hormone cells in anterior pituitary cultures. Mol Cell Endo 1990; 69:179–185.Google Scholar
  51. 51.
    Billestrup N, Gonzalez, Manchon C, Potter E, Vale W Inhibition of somatotroph growth and growth hormone biosynthesis by activin in vitro. Mol Endocrinol 1990; 4:356–362.PubMedGoogle Scholar
  52. 52.
    Bilezikjian LM, Corrigan AZ, Vale W Activin-A modulate growth hormone secretion from cultures of rat anterior pituitary cells. Endocrinology 1990; 126:2369–2376.PubMedGoogle Scholar
  53. 53.
    Sarkar DK, Kim KH, Minami S. Transforming growth factor-β1 messenger RNA and protein expression in the pituitary gland: its action on prolactin secretion and lactotropic growth. Mol Endo 6:1825–1833.Google Scholar
  54. 54.
    Delidow BC, Billis WM, Agarwal P. White. Inhibition of prolactin gene transcription by transforming growth factor- β in GH3 cells. Mol Endo 1991; 5:1716–1722.Google Scholar
  55. 55.
    Samsoondar J. Kobrin MS, Kudlow JE. α-Transforming growth factor secreted by untransformed bovine anterior pituitary cells in culture. J Biol Chem 1986; 261:14408–14413.PubMedGoogle Scholar
  56. 56.
    Finley EL, Ramsdell JS. A transforming growth factor-α pathway is expressed in GH4C1 rat pituitary tumors and appears necessary for tumor formation. Endocrinology 1994; 135:416–422.PubMedGoogle Scholar
  57. 57.
    Kobrin MS, Asa SL, Samsoondar J, Kudlow JE. α-Transforming growth factor in the bovine anterior pituitary gland: secretion by dispersed cells and immunohistochemical localization. Endocrinology 1987; 121:1412–1416.PubMedGoogle Scholar
  58. 58.
    Marquardt H, Hunkapiller MW, Hoodk L.E., Todaro GJ. Rat transforming growth factor type 1: structure and relation to epidermal growth factor. Science 1984; 223:1079–1082.PubMedGoogle Scholar
  59. 59.
    Patterson JC, Childs GV. Nerve growth factor in the anterior pituitary: regulation of secretion. Endocrinology 1994; 135:1697–1704.PubMedGoogle Scholar
  60. 60.
    Patterson JC, Childs GV. Nerve growth factor and its receptor in the anterior pituitary. Endocrinology 1994; 135:1689–1696.PubMedGoogle Scholar
  61. 61.
    Missale C, Boroni F, Frassine M, Caruso A, Spano P. Nerve growth factor promotes the differentiation of pituitary mammotroph cells in vitro. Endocrinology 1995; 136:1205–1213.PubMedGoogle Scholar
  62. 62.
    Borelli E, Sawchenko PE, Evans RM. Pituitary hyperplasia induced by ectopic expression of nerve growth factor. Proc Natl Acad Sci USA 1992; 89:2764–2768.Google Scholar
  63. 63.
    Fan X, Childs GV. Epidermal growth factor and transforming growth factor-α messenger ribonucleic acids and their receptors in the rat anterior pituitary: localization and regulation. Endocrinology 1995; 136:2284–2293.PubMedGoogle Scholar
  64. 64.
    Murdoch GH, Potter E, Nicolaisen AK, Evans RM, Rosenfeld MG. Epidermal growth factor rapidly stimulates prolactin gene transcription. Nature 1982; 300 192–194.PubMedGoogle Scholar
  65. 65.
    Schonbrunn A, Krasnoff M, Westendorf J, Tashjian AJ. Epidermal growth factor and thyrotropin—releasing hormone act similarly on a clonal pituitary cell strain. J Cell Biol 1980; 85:786–797.PubMedGoogle Scholar
  66. 66.
    Johnson L, Baxter J, Vlodavsky I, Gospodrowicz D. Epidermal growth factor and expression of specific genes: effects on cultured rat pituitary cells are dissociable from the mitogenic response. Proc Natl Acad Sci USA 1980; 77:394–398.PubMedGoogle Scholar
  67. 67.
    Childs GV. Epidermal growth factor enhances ACTH secretion and expression of POMC mRNA by corti-cotropes in mixed and enriched cultures. Mol Cell Neurosci 1991; 2:235–241.PubMedGoogle Scholar
  68. 68.
    Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G. Structural characterization and biological functions of fibroblast growth factors. Endocrine Rev 1987; 8:95–114.Google Scholar
  69. 69.
    Gospodarowicz D, Ferrara N. Fibroblast growth factor and the control of pituitary and gonad development and function. Steroid Biochem. 1989; 32:183–191.Google Scholar
  70. 70.
    Rosenfeld MG. POU-domain transcription factors: powerful developmental regulators. Genes Dev 1991; 5:897–907.PubMedGoogle Scholar
  71. 71.
    Bodner M, Castrillo JL, Theill LE, Derrinck T, Ellisman M, Karin M. The pituitary specific transcription factor GHF-1 is a homeobox-containing protein. Cell 1988; 55:505–518.PubMedGoogle Scholar
  72. 72.
    Ingraham HA, Chen RP, Mangalam HP, Elsholtz HP, Flynn SE, Lin CR, Simmons DM, Swanson L, Rosenfeld MG. A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 1988; 55:519–529.PubMedGoogle Scholar
  73. 73.
    Crenshaw EB, III, Kalla K, Simmons DM, Swanson LW, Rosenfeld MG. Cell-specific expression of the prolactin gene in transgenic mice is controlled by synergistic interactions between Pit-1 recognition elements. Genes Dev 1989; 3:959–972.PubMedGoogle Scholar
  74. 74.
    Lira SA, Crenshaw EB, III, Glass CK, Swanson LW, Rosenfeld MG. Identification of rat growth hormone genomic sequence targeting pituitary expression in transgenic mice. Proc Natl Acad Sci USA 1989; 85:4755–4759.Google Scholar
  75. 75.
    Dolle P, Castrillo J-L, Theill LE, Deerinck T, Ellisman M, Karin M. Expression of GHF-1 protein in mouse pituitaries correlates both temporally and spatially with the onset of growth hormone gene activity. Cell 1990; 60:809–820.PubMedGoogle Scholar
  76. 76.
    Lin S-C, Li S, Drolet DW, Rosenfeld MG. Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development 1994; 120:515.PubMedGoogle Scholar
  77. 77.
    Theill LE, Hattori K, Lazzaro D, Castrillo J-L, Karin M. Differential splicing of the GHF-1 primary transcript gives rise to two functionally distinct homeodomain proteins. EMBO J 1992; 11:2261–2269.PubMedGoogle Scholar
  78. 78.
    Morris AE, Kloss B, McChesney RE, Bancroft C, Chasin LA. An alternatively spliced Pit-1 isoform altered in its ability to trans-activate. Nucleic Acids Res 1992; 20:1355–1361.PubMedGoogle Scholar
  79. 79.
    Konzak KE, Moore DD. Functional isoforms of Pit-1 generated by alternative mRNA splicing. Mol Endocrinol 6:241–247.Google Scholar
  80. 80.
    Haugen BR, Wood WM, Gordon DF, Ridgway EC. A thyrotrope-specific variant of Pit-1 transactivates the thyrotropin β promoter. J Biol Chem 1993; 268:20,818–20,824.Google Scholar
  81. 81.
    Haugen BR, Gordon DF, Nelson AR, Wood WM, Ridgway EC. The combination of Pit-1 and Pit-IT have a synergistic stimulatory effect on the thyrotropin β-subunit promoter but not the growth hormone or prolactin promoters. Mol Endocrinol 1994; 8:1574–1582.PubMedGoogle Scholar
  82. 82.
    Rhodes SJ, Chen R, DiMattia GE, Scully KM, Kalla KA, Lin S-C, Yu VC, Rosenfeld MG. A tissue-specific enhancer confers Pit-1-dependent morphogen inducibility and autoregulation on the pit-1 gene. Genes Dev 1993; 7:913–932.PubMedGoogle Scholar
  83. 83.
    Castrillo JL, Theill LE, Karin M. Function of the homeodomain protein GHF1 in pituitary cell proliferation. Science 1991; 253:197–199.PubMedGoogle Scholar
  84. 84.
    Day RN, Koikw A, Sakai M, Muramatsu M, Maurer RA. Both Pit-1 and the estrogen receptor are required for estrogen responsiveness of the rat prolactin gene. Mol Endocrin 1990; 4:1964–1971.Google Scholar
  85. 85.
    Schaufele F, West BL, Baxter JD. Synergistic activation of the rat growth hormone promoter by Pit-1 and the thyroid hormone receptor. Mol Endocrinol 1992; 6:656–665.PubMedGoogle Scholar
  86. 86.
    He X, Treacy MM, Simmons DM, Ingraham HA, Swanson LW, Rosenfeld MG. Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature 1989; 340:35–42.PubMedGoogle Scholar
  87. 87.
    Elsholtz HP, Albert VR, Treacy MN, Rosenfeld MG. A two-base change in a POU factor-binding site switches pituitary-specific to lymphoid-specific gene expression. Genes Dev 1990; 4:43–51.PubMedGoogle Scholar
  88. 88.
    Chen C, Ingraham HA, Treacy MN, Albert VA, Wilson L, Rosenfeld MG. The pituitary POU-domain protein Pit-1 can positively and negatively regulate transcription of its own promoter. Nature 1990; 346:583–586.PubMedGoogle Scholar
  89. 89.
    Voss JW, Wilson L, Rosenfeld MG. POU-domain proteins Pit-1 and Oct-1 interact to form a heteromeric complex and can cooperate to induce expression of the prolactin promoter. Genes Dev 1991; 5: 1309–1320.PubMedGoogle Scholar
  90. 90.
    Bach I, Rhodes SJ, Pearse RV, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Natl Acad Sci 1995; 92:2720–2724.PubMedGoogle Scholar
  91. 91.
    Busch SJ, Sassone-Corsi P. Dimers, leucine zippers and DNA-binding domains. Trends Genet 1990; 6:36–40.PubMedGoogle Scholar
  92. 92.
    Drolet DW, Scully KM, Simmons DM, Wegner M, Chu K, Swanson LW, Rosenfeld MG. TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins. Genes Dev 1991; 5:1739–1753.PubMedGoogle Scholar
  93. 93.
    Delegeane AM, Ferland LH, Mellon PL. Tissue specific enhancer of the human glycoprotein hormone a subunit gene: dependence on cAMP inducible elements. Mol Cell Biol 1987; 7:3994–4002.PubMedGoogle Scholar
  94. 94.
    McCormick A, Brady H. Theill LE, Karin M. Regulation of the pituitary-specific homeobox gene GHF-1 by cell-autonomous and environmental cues. Nature 1990; 345:829–832.PubMedGoogle Scholar
  95. 95.
    Bilezikjian LM, Erlichman J, Fleischer N. Vale W Differential activation of type I and type II 3′, 5′-cyclic adenosine monophosphate -dependent protein kinases by growth hormone releasing factor. Mol Endocrinology 1987; 1:137–146.Google Scholar
  96. 96.
    Bilezikjian LM, Vale W Stimulation of adenosine 3′,5′ -monophosphate production by growth hormone-releasing factor and its inhibition by somatostatin in anterior pituitary cells in vitro. Endocrinology 1983; 113:1726–1731.PubMedGoogle Scholar
  97. 97.
    Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR. Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. 1991; Nature 350:622–624.PubMedGoogle Scholar
  98. 98.
    Bertherat J. Chanson P, Montminy M. The cyclic,adenosine 3′,5′-monophosphate responsive factor CREB is constitutively activated in human somatotroph adenomas. Mol Endocrinol 1995; 9:777–783.PubMedGoogle Scholar
  99. 99.
    Schoderbek WE, Kim KE, Ridgway EC, Mellon PL, Maurer RA. Analysis of DNA sequences required for pituitary-specific expression of the glycoprotein hormone α-subunit gene. Mol Endocrinol 1992; 6:893–903.PubMedGoogle Scholar
  100. 100.
    Akerblom IE, Slater EP, Becto M, Baxter JD, Mellon PL. Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer. Science 1988; 241:350–353.PubMedGoogle Scholar
  101. 101.
    Therrien M, Drouin J. Cell-specific helix-loop-helix factor required for pituitary expression of the proopiomelanocortin gene. Mol Cell Biol 1993; 13:2342–2353.PubMedGoogle Scholar
  102. 102.
    Tremblay J, Lamonerie T, Lanctot C, Therrien M, Drouin J. A novel homeobox transcription factor is expressed in early pituitary development and is a major determinant for cell-specific transcription of the proopiomelanocortin gene. Endocr Soc Meeting Abstr 1995; OR 18–2.Google Scholar
  103. 103.
    Jackson SM, Barnhart KM, Mellon PL, Gutierrez-Hartmann A, Hoeffler JP. Helix-loop-helix proteins are present and differentially expressed in different cell lines from the anterior pituitary. Mol Cell Endocrinology 1993; 96:167–176.Google Scholar
  104. 104.
    Jackson SM, Gutierrez-Hartmann A, Hoeffler JP. Upstream stimulatory factor, a basic helix loop helix zipper protein, regulates the activity of the alpha-glycoprotein hormone subunit gene in pituitary cells. Mol Endocrinol 1995; 9:278–291.PubMedGoogle Scholar
  105. 105.
    Lipkin SM, Naar AM, Kalla KA, Sack RA, Rosenfeld MG. Identification of a novel zinc finger protein binding a conserved element critical for Pit-1-dependent growth hormone gene expression. Genes Dev 1993;7:1674–1687.PubMedGoogle Scholar
  106. 106.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: The second decade. Cell 1995; 83:835–839.PubMedGoogle Scholar
  107. 107.
    Green S, Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genetics 1988; 4:309–314.Google Scholar
  108. 108.
    Horn F, Windle JJ, Barnhart KM, Mellon PL. Tissue-specific gene expression in the pituitary: The glycoprotein hormone α-subunit gene is regulated by a gonadotrope-specific protein. Mol Cell Biol 1992; 12:2143–2153.PubMedGoogle Scholar
  109. 109.
    Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen W-H, Nachtigal MW, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor L acts at multiple levels of the reproductive axis. Genes Dev 1994; 8:2302–2312.PubMedGoogle Scholar
  110. 110.
    Honda S-I, Morohashi K-I, Nomura M, Takeya H. Kitajima M, Omura T. Ad4BP regulating steriodogenic P-450 gene is a member of steroid hormone receptor superfamily. J Biol Chem 1993; 268:7494–7502.PubMedGoogle Scholar
  111. 111.
    Lala DS, Rice DA, Parker KL. Steriodogenic factor 1, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor 1. Mol Endocrinol 1993; 6:1249–1258.Google Scholar
  112. 112.
    Japon MG, Rubenstein M, Low MJ. In situ hybridization analysis of anterior pituitary homone gene expression during fetal mouse development. J Histochem Cytochem 1994; 42:1117–1125.PubMedGoogle Scholar
  113. 113.
    Shupnik MA, Fallest PC. Steriodogenic factor-1 binds to a region of the rat LHβ gene which confers a synergistic response to cyclic amp and protein kinase C activation. Endocr Soc Meeting Abst 1995; P1-521.Google Scholar
  114. 114.
    Shupnik MA, Gharib SD, Chin WW. Divergent effects of estradiol on gonadotropin gene transcription in pituitary fragments. Mol Endo 1989; 3:474–480.Google Scholar
  115. 115.
    Shupnik MA, Weinmann CM, Notides AC, Chin WW. An upstream region of the rat luteinizing hormone β gene binds estrogen receptor and confers estrogen responsiveness. J Biol Chem 1989; 264:80–86.PubMedGoogle Scholar
  116. 116.
    Shupnik MA, Rosenzweig BA. Identification of an estrogen-responsive element in the rat LHoc gene. J Biol Chem 1991; 266:17084–17091.PubMedGoogle Scholar
  117. 117.
    Friend KE, Chiou YK, Lopes MBS, Laws ER, Jr., Hughes KM, Shupnik MA. Estrogen receptor expression in human pituitary: correlation with immunohistochemistry in normal tissue, and immunohistochem-istry and morphology in macroadenomas. J Clin Endo Metab 1994; 78: 1497–1504.Google Scholar
  118. 118.
    Stefaneanu L, Kovacs K, Horvath E, Lloyd RV, Buchfelder M, Fahlbusch R. Smyth H. In situ hybridization study of estrogen receptor messenger ribonucleic acid in human adenohypophysial cells and pituitary adenomas. J Clin Endo Metab 1994; 78:83–88.Google Scholar
  119. 119.
    Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot. Cell 1995; 83:851–857.PubMedGoogle Scholar
  120. 120.
    Drouin J, Trifiro MA, Plante RK, Nemer M, Eriksson P, Wrange O. Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. Mol Cell Biol 1989; 9:5303–5314.Google Scholar
  121. 121.
    Elsholtz HP. Molecular biology of prolactin: Cell-specific and endocrine regulators of the prolactin gene. Seminars of Reprod Endocrinol 1992; 10:183–195.Google Scholar
  122. 122.
    Cintra A, Solfrini V, Bunnemann B, Okret S, Bortolotti F. Gustafsson J-A, Fuxe K. Prenatal development of glucocorticoid receptor gene expression and immunoreactivity in the rat brain and pituitary gland: a combined in situ hybridization and immunocytochemical analysis. Neuroendocrinology 1993; 57:1133–1147.PubMedGoogle Scholar
  123. 123.
    Meaney MJ, Sapolsky RM, McEwen BS. The development of the glucocorticoid receptor system in the rat limbic brain, I. Ontogeny and autoregulation. Dev Brain Res 1985; 18:159–164.Google Scholar
  124. 124.
    Wondisford FE, Farr EA, Radovick S, Steinfelder HJ, Moates JM, McClaskey JH, Weintraub BD. Thyroid hormone inhibition of human thyrotropin β-subunit gene expression is mdiated by a cis-acting element located in the first exon. J Biol Chem 1989; 264:14601–14604.PubMedGoogle Scholar
  125. 125.
    Chatterjee VKK, Lee J-K, Rentoumis A, Jameson JL. Negative regulation of the thyroid-stimulating hormone a gene by thyroid hormone: receptor interaction adjacent to the TATA box. Proc Natl Acad Sci USA 1989; 86:9114–9118.PubMedGoogle Scholar
  126. 126.
    Carr FE, Burnside J, Chin WW. Thyroid hormones regulate rat thyrotropin S gene promoter activity expressed in GH3 cells. Mol Endo 1989; 3:709–716.Google Scholar
  127. 127.
    Burnside J, Darling DS, Carr FE, Chin WW. Thyroid hormone regulation of the rat glycoprotein hormone α-subunit gene promoter activity. J Biol Chem 1989; 264:6886–6891.PubMedGoogle Scholar
  128. 128.
    Brent GA, Harney JW, Chen Y, Warne RG, Moore DD, Larsen PR. Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element. Mol Endocrinol 1989; 3:1996–2007.PubMedGoogle Scholar
  129. 129.
    Glass CK, Franco R, Weinberger C, Albeit VR, Evans RM, Rosenfeld MG. A c-erbA binding site in rat growth hormone gene mediates trans-activation by thyroid hormone. Nature 1987; 329:738–741.PubMedGoogle Scholar
  130. 130.
    Sporn MB, Roberts AB. Role of retinoids in differentiation and carcinogenesis. Cancer Res. 1983; 43:3034–3040.PubMedGoogle Scholar
  131. 131.
    Macleod K, Leprince D, Stehelin D. The ets gene family. Trends Biochem Sci 1992; 17:251–256.PubMedGoogle Scholar
  132. 132.
    Wasylyk B. Hahn SH, Giovane A. The Ets family of transcription factors. Eur J Biochem 1993; 211:7–18.PubMedGoogle Scholar
  133. 133.
    Bradford AP, Conrad KE, Wasylyk C, Wasylyk B, Gutierrez-Hartmann A. Functional interaction of c-Ets-1 and GHF-1/Pit-1 mediates Ras activation of pituitary-specific gene expression: Mapping of the essential c-Ets-1 domain. Mol Cell Biol 1995; 15:2849–2857.PubMedGoogle Scholar
  134. 134.
    Bradford AP unpublished results.Google Scholar
  135. 135.
    Maroulakou IG, Papas TS, Green JE. Differential expression of ets-1 and ets-2 protooncogenes during murine embryogenesis 1994; 1551–1565.Google Scholar
  136. 136.
    Abrahams JJ, Trefelner E, Boulware SD. Idiopathic growth hormone deficiency: MR findings in 35 patients. American J Neurorad 1991; 12:155–160.Google Scholar
  137. 137.
    Kuroiwa T, Yasufumi O, Hasuo K, Yasumori K, Mizushima A, Masuda K. MR imaging of pituitary dwarfism. American J Neurorad 1991; 12:161–164.Google Scholar
  138. 138.
    Root AW. Magnetic resonance imaging in hypopituitarism. J Clin Endocrinol Metab 1991; 72:10,11.PubMedGoogle Scholar
  139. 139.
    Proto G, Mazzolini A, Grimaldi F. Bertolissi F, Pozzi-Mucelli RS, Magnaldi S. Idiopathic anterior hypopituitarism: magnetic resonance imaging and clinical correlation. J Endocrinol Invest 1992; 15:283–287.PubMedGoogle Scholar
  140. 140.
    Brown RS, Bhatia V, Hayes E. An apparent cluster of congenital hypopituitarism in central Massachusetts: magnetic resonance imaging and hormonal studies. J Clin Endocrinol Metab 1991; 72:12–18.PubMedGoogle Scholar
  141. 141.
    Radovick S, Nations M, Du Y, Berg LA, Weintraub BD, Wondisford FE. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 1992; 257:1115–1118.PubMedGoogle Scholar
  142. 142.
    Cohen LE, Wondisford FE, Salvatoni A, Maghnie M, Brucker-Davis F, Weintraub BD, Radovick S. A “hot spot” in the Pit-1 gene responsible for combined pituitary hormone deficiency: Clinical and molecular correlates. J Clin Endocrin Metab 1995; 80:679–684.Google Scholar
  143. 143.
    Pfaffle RW, DiMattia GE, Parks JS, Brown MR, Wit JM, Jansen M, Van der Nat H, Van den Brande JL, Rosenfeld MG, Ingraham HA. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992; 257:1118–1121.PubMedGoogle Scholar
  144. 144.
    Labbe A, Dubray C, Gaillard G, Besse G, Assali P, Malpucch G. Familial growth retardation with isolated thyroid-stimulating hormone deficiency. Clin Pediatr 1984; 23:675–678.Google Scholar
  145. 145.
    Hayashizaki Y, Hiraoka Y, Tatsumi K, Hashimoto T, Furuyama J-I, Miyai K, Nishijo K, Matsuura M, Kohno H. Labbe E, Matsubara K. Deoxyribonucleic acid analyses of five families with familial inherited thyroid stimulating hormone deficiency. J Clin Endocrinol Metab 1990; 71:792–796.PubMedGoogle Scholar
  146. 146.
    Hayashizaki Y, Miyai K, Onishi T, Kumahara Y, Effects of corticotrophin releasing factor and growth hormone releasing factor on pituitary hormone secretion in patients with congenital thyrotropin (TSH) deficiency. Horm Metab Res 1986; 18:842–846.Google Scholar
  147. 147.
    Miyai K, Azukizawa M, Kumahara Y Familial isolated thyrotropin deficiency with cretinism. N Engl J Med 1971; 285:1043–1048.PubMedGoogle Scholar
  148. 148.
    Hayashizaki Y, Hiraoka Y, Endo Y, Matsubara K. Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the β-subunit. EMBO J 1989; 8:2291–2296.PubMedGoogle Scholar
  149. 149.
    Dacou-Voutekais C, Feltquate DM, Drakopoulou M, Kourides IA, Dracopoli NC. Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone β-subunit gene. Am J Human Genet 1990; 46:988–993.Google Scholar
  150. 150.
    Kallman FJ, Schenfeld WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Ment Defic 1944; 48:203–236.Google Scholar
  151. 151.
    Crowley WF, Jameson JL. Gonadotlopin-releasing hormone deficiency: perspectives from clinical investigation. Endocr Rev 1992; 13:635–640.PubMedGoogle Scholar
  152. 152.
    Schwanzel-Fukuda M, Jorgenson KL, Bergen HT, Weesner GD, Pfaff DW. Biology of normal luteinizing hormone-releasing hormone neurons during and after their migration from olfactory placode. Endocr Rev 1992; 13:623–634.PubMedGoogle Scholar
  153. 153.
    Alexander JM, Biller BM, Bikkal H, Zervas NT, Arnold A, Klibanski A. Clinically nonfunctioning pituitary tumors are monoclonal in origin. J Clin Invest 1990; 86:336–340.PubMedGoogle Scholar
  154. 154.
    Vallar L, Spada A, Giannattasio G. Altered Gsoc adenylate cyclase activity in human GH secreting adenomas. Nature 1987; 330:566–568.PubMedGoogle Scholar
  155. 155.
    Spada A, Arosis M, Bassetti M, Vallar L, Clementi E, Bazzoni N. Mutations in the alpha subunit of the stimulatory regulatory protein of adenylyl cyclase (Gs) in human GH-secreting pituitary adenomas. Biochemical, clinical and morphological aspects. Pathol Res Pract 187:567–570.Google Scholar
  156. 156.
    Gonsky R, Herman V, Melmed S, Fagin J. Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 1991; 5:1587–1695.Google Scholar
  157. 157.
    U HS, Kelley P, Lee WH. Abnormalities of the human growth hormone gene and protooncogenes in some human pituitary adenomas. Mol Endocrinol 1988; 2:85–89.Google Scholar
  158. 158.
    Birman P, Michard M, Li JY, Peillon F, Bression D. Epidermal growth factor-binding sites, present in normal human and rat pituitaries, are absent in human pituitary adenomas. J Clin Endocrinol Metab 1987; 65:275–281.PubMedGoogle Scholar
  159. 159.
    Alvaro V, Levy L, Dubray C. Invasive human pituitary tumors express a point-mutated α-protein kinase-C. J Clin Endocrinol Metab 1993; 77:1125–1129.PubMedGoogle Scholar
  160. 160.
    Karga HJ, Alexander JM, Hedley-Whyte ET, Klibanski A, Jameson JL. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 1992; 75:914–919.Google Scholar
  161. 161.
    Cai WY, Alexander JM, Hedley-Whyte ET, Scheithauer BW, Jameson JL, Zervas NT, Klibanski A. Ras mutations in human prolactinomas and pituitary carcinomas. J Clin Endocrinol Metab 1994; 78:89–93.PubMedGoogle Scholar
  162. 162.
    Pei L, Melmed S. Scheithauer B. Kovacs K, Prager D. H-Ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 1994; 78:847–854.Google Scholar
  163. 163.
    Boggild MD, Jenkinson S. Pistorello M. Molecular genetic studies of sporadic pituitary tumors. J Clin Endocrinol Metab 1994; 78:387–392.PubMedGoogle Scholar
  164. 164.
    Kontogeorgos G. Kovacs K, Scheithauer BW, Rologis D, Orphanidis G. α-subunit immunoreactivity in plurihormonal pituitary adenomas of patients with acromegaly. Mod Pathol 1991; 4:191–195.PubMedGoogle Scholar
  165. 165.
    Furuhata S. Kameya T. Otani M, Toya S. Prolactin presents in all pituitary adenomas of acromegalic patients. Hum Pathol 1993; 24:10–15.PubMedGoogle Scholar
  166. 166.
    Kourides IA, Ridgway EC, Weintraub BD, Bigos ST, Gershengorn MC, Maloof R. Thyrotropin induced hyperthyroidism: use of alpha and beta subunit levels to identify patients with pituitary tumors. J Clin Endocrinol Metab 1977; 45:534–543.PubMedGoogle Scholar
  167. 167.
    Lamberg BA, Pelkonen R. Gordin A. Hyperthyroidism and acromegaly caused by pituitary TSH- and GH-secreting tumors. Acta Endocrinol 1983; 103:7–14.PubMedGoogle Scholar
  168. 168.
    Kuzuya N, Inque K, Ishibashi M, Murayama Y, Koide Y, Ito K, Yamaji T, Yamashita K. Endocrine and immunohistochemical studies on thyrotropin (TSH)-secreting pituitary adenomas: Responses of TSH, α-subunit, and growth hormone to hypothalamic releasing hormones and their distribution in adenoma cells. J Clin Endocrin Metab 1990; 71:1103–1111.Google Scholar
  169. 169.
    Berg KK, Scheithauer BW, Felix I, Kovacs K, Horvath E, Klee GG, Laws ER. Pituitary adenomas that produce adrenocorticotropic hormone and α-subunit: clinicopathological, immunohistochemical, ultra-structural, and immunoelectron microscopic studies in nine cases. Neurosurg 1990; 26:397–403.Google Scholar
  170. 170.
    Oppenheim DS, Kana AR, Sangha JS, Klibanski A. Prevalence of α-subunit hypersecretion in patients with pituitary tumors: Clinically nonfunctioning and somatotroph adenomas. J Clin Endocrinol Metab 1990; 70:859–864.PubMedGoogle Scholar
  171. 171.
    King JWB. Pygmy, a dwarfing gene in the house mouse. J Heredity 1950; 41:249–252.Google Scholar
  172. 172.
    Koto M, Sato T. Okamoto M, Adachi J. Rdw rats, a new hereditary dwarf model in the rat. Experimental Animals 1988; 37:21–30.PubMedGoogle Scholar
  173. 173.
    Shibayama K, Ohyama Y Ono M, Furudate S. Expression of mRNA coding for pituitary hormone and pituitary-specific transcription factor in the pituitary gland of the rdw rat with hereditary dwarfism. J Endocrin 1993; 138:301–313.Google Scholar
  174. 174.
    Ono M, Harigai T. Furudate S. Pituitary-specific transcription factor Pit-1 in the rdw rat with growth hormone- and prolactin-deficient dwarfism. J Endocrin 1994; 143:479–487.Google Scholar
  175. 175.
    Okuma S. Kawashima S. Spontaneous dwarf rat. Exp Anim 1980; 29:301–304.Google Scholar
  176. 176.
    Ohta K, Nobukuni Y, Mitsubchi H, Fujimoto S, Matsuo N, Inagaki H, Endo F, Matsuda I. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem Biophys Res Commun 1992; 189:851–855.PubMedGoogle Scholar
  177. 177.
    Tatsumi K, Miyai K, Notomi T. Kaibe K, Amino N. Mizuno Y. Kohno H. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nature Genet 1992; 1:56–58.PubMedGoogle Scholar
  178. 178.
    Hammer RE, Brinster RL, Rosenfeld MC;, Evans RM, Mayo KE. Expression of human growth hormone-releasing factor in transgenic mice results in increased somatic growth. Nature 1985; 315:413–416.PubMedGoogle Scholar
  179. 179.
    Behringer RR, Mathews LS, Palmiter RD, Brinster RL. Dwarf mice produced by genetic ablation of growth hormone-expressing cells. Genes Dev 1988; 2:453–461.PubMedGoogle Scholar
  180. 180.
    Lew D, Brady H, Klausing K, Yaginuma K, Theill LE, Stauber C, Karin M, Mellon PL. GHF-1-promoter-targeted immortalization of a somatotropic progenitor cell results in dwarfism in transgenic mice. Genes Dev 1993; 7:683–693.PubMedGoogle Scholar

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© Humana Press Inc. 1997

Authors and Affiliations

  • Cheryl A. Pickeet
  • Authur Gutierrez-Hartmann

There are no affiliations available

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