Skip to main content

Transgenic Approaches to Study Developmental Expression and Regulation of the Gonadotropin Genes

  • Chapter
  • 97 Accesses

Part of the book series: Contemporary Endocrinology ((COE,volume 22))

Abstract

In the past decade, transgenic animals have evolved as key tools for studies of the development, molecular biology, and function of the reproductive system. Probably the single most important contribution of transgenics to the investigation of gonadotrophs and the gonadotropin genes has been the development through targeted oncogenesis of differentiated pituitary gonadotroph cell lines, specifically the α-T3 (1) and LβT2 (2) cell lines. This chapter reviews the application of these cell lines and in vivo transgenic expression systems to the understanding of the physiological regulation of the glycoprotein hormone α-subunit, luteinizing hormone β (LHβ), and follicle-stimulating hormone β (FSHβ) genes, and the detailed analysis of promoter elements involved in the complex integration of signals for α-subunit gene transcription. Other advances that have been possible as a direct result of the α-T3 cell line include the cloning of LH-2, a novel LIM/homeodomain transcription factor (3), and the gonadotropin-releasing hormone (GnRH) receptor cDNAs (4,5), as well as a detailed ding of the intracellular signaling pathways involved in GnRH action (for a review see ref. 6).

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Windle JJ, Weiner RI, Mellon PL. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol Endocrinol 1990; 4: 597–603.

    Article  PubMed  CAS  Google Scholar 

  2. Turgeon JL, Kimura Y, Waring DW, Mellon PL. Steroid and pulsatile gonadotropin-releasing hormone (GnRH) regulation of luteinizing hormone and GnRH receptor in a novel gonadotrope cell line. Mol Endocrinol 1996; 10: 439–450.

    Article  PubMed  CAS  Google Scholar 

  3. Roberson MS, Schoderbek WE, Tremml G, Maurer RA. Activation of the glycoprotein hormone a-subunit promoter by a LIM-homeodomain transcription factor. Mol Cell Biol 1994; 14: 2985–2993.

    PubMed  CAS  Google Scholar 

  4. Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL, Flanagan CA, Dong K, Gillo B, Sealfon SC. Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol Endocrinol 1992; 6: 1163–1169.

    Article  PubMed  CAS  Google Scholar 

  5. Reinhart J, Mertz LM, Catt KJ. Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor. J Biol Chem 1992; 267:21,281–21,284.

    CAS  Google Scholar 

  6. Kaiser UB, Conn PM, Chin WW. Studies of gonadotropin-releasing hormone (GnRH) action using GnRH receptor-expressing pituitary cell lines. Endocr Rev 1997; 18: 46–70.

    Article  PubMed  CAS  Google Scholar 

  7. Camper SA, Saunders TL, Kendall SK, Keri RA, Seasholtz AF, Gordon DG, Birkmeier TS, Keegan CE, Karolyi IJ, Roller ML, Burrows HL, Samuelson LC. Implementing transgenic and embryonic stem cell technology to study gene expression, cell-cell interactions and gene function. Biol Reprod 1995; 52: 246–257.

    Article  PubMed  CAS  Google Scholar 

  8. Alarid ET, Mellon PL. Down-regulation of the gonadotropin-releasing hormone receptor messenger ribonucleic acid by activation of adenylyl cyclase in aT3–1 pituitary gonadotrope cells. Endocrinology 1995; 136: 1361–1366.

    Article  PubMed  CAS  Google Scholar 

  9. Braden TD, Conn PM. Altered rate of synthesis of gonadotropin-releasing hormone receptors: effects of homologous hormone appear independent of extracellular calcium. Endocrinology 1990; 126: 2577–2582.

    Article  PubMed  CAS  Google Scholar 

  10. Hille B, Tse A, Tse FW, Bosma MM. Signaling mechanisms during the response of pituitary gonadotropes to GnRH. Recent Prog Horm Res 1995; 50: 75–95.

    PubMed  CAS  Google Scholar 

  11. Merelli F, Stojilkovic SS, Toshihiko I, Krsmanovic LZ, Zheng L, Mellon PL, Catt KJ. Gonadotropinreleasing hormone-induced calcium signaling in clonal pituitary gonadotrophs. Endocrinology 1992; 131: 925–932.

    Article  PubMed  CAS  Google Scholar 

  12. Weiss J, Crowley WF, Halvorson LM, Jameson JL. Perifusion of rat pituitary cells with gonadotropinreleasing hormone, activin, and inhibin reveals distinct effects on gonadotropin gene expression and secretion. Endocrinology 1993; 132: 2307–2311.

    Article  PubMed  CAS  Google Scholar 

  13. Mores N, Krsmanovic LZ, Call KJ. Activation of LH receptors expressed in GnRH neurons stimulates cyclic AMP production and inhibits pulsatile neuropeptide release. Endocrinology 1996; 137: 5731–5734.

    Article  PubMed  CAS  Google Scholar 

  14. Magis W, Fiering S, Groudine M, Martin DI. An upstream activator of transcription coordinately increases the level and epigenetic stability of gene expression. Proc Natl Acad Sci USA 1996; 93:13, 914–13, 918.

    Google Scholar 

  15. Wilke T, Brinster R, Palmiter R. Germline and somatic mosaicism in transgenic mice. Dev Biol 1986; 118: 9–18.

    Article  Google Scholar 

  16. Milot E. Heterochromatin effects on the frequency and duration of LCR-mediated gene transcription. Cell 1996; 87: 105–114.

    Article  PubMed  CAS  Google Scholar 

  17. Palmiter RD, Sandgren EP, Koeller DM, Brinster RL. Distal regulatory elements from the mouse metallothionein locus stimulate gene expression in transgenic mice. Mol Cell Biol 1993; 13: 5266–5275.

    PubMed  CAS  Google Scholar 

  18. Brinster RL, Allen JM, Behringer RR, Gelinas RE, Palmiter RD. Introns increase transcriptional efficiency in transgenic mice. Proc Natl Acad Sci USA 1988; 85: 836–840.

    Article  PubMed  CAS  Google Scholar 

  19. Low MJ, Stork PJ, Hammer RE, Brinster RL, Warhol MJ, Mandel G, Goodman RH. Somatostatin is targeted to the regulated secretory pathway of gonadotrophs in transgenic mice expressing a metallothionein-somatostatin gene. J Biol Chem 1986; 261:16, 260–16, 263.

    Google Scholar 

  20. Low MJ, Lechan RM, Hammer RE, Brinster RL, Habener JF, Mandel G, Goodman RH. Gonadotrophspecific expression of metallothionein fusion genes in pituitaries of transgenic mice. Science 1986; 231: 1002–1004.

    Article  PubMed  CAS  Google Scholar 

  21. Low MJ, Goodman RH, Ebert KM. Cryptic human growth hormone gene sequences direct gonadotroph-specific expression in transgenic mice. Mol Endocrinol 1989; 3: 2028–2033.

    Article  PubMed  CAS  Google Scholar 

  22. Kendall SK, Gordon DF, Birkmeier TS, Petrey D, Sarapura VD, O’Shea KS, Wood WM, Lloyd RV, Ridgway EC, Camper SA. Enhancer-mediated high level expression of mouse pituitary glycoprotein hormone a-subunit transgene in thyrotropes, gonadotropes, and developing pituitary gland. Mol Endocrinol 1994; 8: 1420–1433.

    Article  PubMed  CAS  Google Scholar 

  23. Albanese C, Colin IM, Crowley WF, Ito M, Pestell RG, Weiss J, Jameson JL. The gonadotropin genes: evolution of distinct mechanisms for hormonal control. Recent Prog Horm Res 1996; 54: 23–61.

    Google Scholar 

  24. Fox M, Solter D. Expression and regulation of the pituitary-and placenta-specific human glycoprotein hormone alpha-subunit gene is restricted to the pituitary in transgenic mice. Mol Cell Biol 1988; 8: 5470–5476.

    PubMed  CAS  Google Scholar 

  25. Hamernik DL, Keri RA, Clay CM, Clay JN, Sherman GB, Sawyer HR, Nett TM, Nilson JH. Gonadotrope-and thyrotrope-specific expression of the human and bovine glycoprotein hormone a-subunit genes is regulated by distinct cis-acting elements. Mol Endocrinol 1992; 6: 1745–1755.

    Article  PubMed  CAS  Google Scholar 

  26. Bokar JA, Keri RA, Farmerie TA, Fenstermaker RA, Andersen B, Hamernik DL, Yun J, Wagner T, Nilson JH. Expression of the glycoprotein hormone a-subunit gene in the placenta requires a functional cyclic AMP response element, whereas a different cis-acting element mediates pituitary-specific expression. Mol Cell Biol 1989; 9: 5113–5122.

    PubMed  CAS  Google Scholar 

  27. Barnhart KM, Mellon PL. The orphan nuclear receptor, steroidogenic factor-1, regulates the glycoprotein hormone a-subunit gene in pituitary gonadotropes. Mol Endocrinol 1994; 8: 878–885.

    Article  PubMed  CAS  Google Scholar 

  28. Andersen B, Kennedy GC, Nilson JH. A cis-acting element located between the cAMP response elements and CCAAT box augments cell-specific expression of the glycoprotein hormone a subunit gene. J Biol Chem 1990; 165:21,874–21,880.

    Google Scholar 

  29. Nilson JH, Bokar JA, Andersen B, Bohinski R, Kennedy G, Keri RA, Farmerie TA, Fenstermaker RA. CRE-Binding proteins interact cooperatively to enhance placental-specific expression of the glycoprotein hormone alpha-subunit gene. Ann NY Acad Sci 1989; 564: 77–85.

    Article  PubMed  CAS  Google Scholar 

  30. Drust DS, Troccoli NM, Jameson JL. Binding specificity of cyclic adenosine 3’, 5’-monophosphateresponsive element (CRE)-binding proteins and activating transcription factors to naturally occurring CRE sequence variants. Mol Endocrinol 1991; 5: 1541–1551.

    Article  PubMed  CAS  Google Scholar 

  31. Heckert LL, Schultz K, Nilson HJ. The cAMP response elements of the a subunit gene bind similar proteins in trophoblasts and gonadotropes but have distinct functional sequence requirements. J Biol Chem 1996; 271:31,650–31,656.

    CAS  Google Scholar 

  32. Delegeane AM, Ferland LH, Mellon PL. Tissue-specific enhancer of the human glycoprotein hormone alpha-subunit gene: dependence on cyclic AMP-inducible elements. Mol Cell Biol 1987; 7: 3994–4002.

    PubMed  CAS  Google Scholar 

  33. Pittman RH, Clay CM, Farmerie TA, Nilson JH. Functional analysis of the placenta-specific enhancer of the human glycoprotein hormone a subunit gene. J Biol Chem 1994; 269:19,360–19,368.

    CAS  Google Scholar 

  34. Steger DJ, Hecht JH, Mellon PL. GATA-binding proteins regulate the human gonadotropin a-subunit gene in the placenta and pituitary gland. Mol Cell Biol 1994; 14: 5592–5602.

    PubMed  CAS  Google Scholar 

  35. Schoderbek WE, Kim KE, Ridgway EC, Mellon PL, Maurer RA. Analysis of DNA sequences required for pituitary-specific expression of the glycoprotein hormone a-subunit gene. Mol Endocrinol 1992; 6: 893–903.

    Article  PubMed  CAS  Google Scholar 

  36. Horn F, Windle JJ, Barnhart KM, Mellon PL. Tissue-specific gene expression in the pituitary: the glycoprotein hormone a-subunit gene is regulated by a gonadotrope-specific protein. Mol Cell Biol 1992; 12: 2143–2153.

    PubMed  CAS  Google Scholar 

  37. Heckert LL, Schultz K, Nilson JH. Different composite regulatory elements direct expression of the human a subunit gene to pituitary and placenta. J Biol Chem 1995; 270:26,497–26,504.

    Google Scholar 

  38. Jackson S, Gutierrez-Hartmann A, Hoeffler J. Upstream stimulatory factor, a basic-helix-loop-helixzipper protein, regulates the activity of the a-glycoprotein hormone subunit gene in pituitary cells. Mol Endocrinol 1995; 9: 278–291.

    Article  PubMed  CAS  Google Scholar 

  39. Brinkmeier ML, Gordon DF, Dowding JM, Saunders TL, Kendall SK, Sarapura VD, Wood WM, Ridgway EC, Camper SA. Cell specific expression of the mouse glycoprotein hormone a-subunit gene requires multiple interacting DNA elements in transgenic mice and cultured cells. Mol Endocrinol 1998; 12: 622–633.

    Article  PubMed  CAS  Google Scholar 

  40. Schoderbek WE, Roberson MS, Maurer RA. Two different DNA elements mediate gonadotropin releasing hormone effects on expression of the glycoprotein hormone a-subunit gene. J Biol Chem 1993; 268: 3903–3910.

    PubMed  CAS  Google Scholar 

  41. Gharib SD, Wierman ME, Shupnik MA, Chin WW. Molecular biology of the pituitary gonadotropins. Endocr Rev 1990; 11: 177–199.

    Article  PubMed  CAS  Google Scholar 

  42. Huang ZH, Lei ZM, Rao CV. Novel independent and synergistic regulation of gonadotropin-a subunit gene by luteinizing hormone/human choriogonadotropin and gonadotropin releasing hormone in the aT3–1 gonadotrope cells. Mol Cell Endocrinol 1997; 130: 23–31.

    Article  PubMed  CAS  Google Scholar 

  43. Kay TWH, Chedrese Pi, Jameson JL. Gonadotropin-releasing hormone causes transcriptional stimulation followed by desensitization of the glycoprotein hormone a promoter in transfected aT3 gonadotrope cells. Mol Endocrinol 1994; 134: 568–573.

    Article  CAS  Google Scholar 

  44. Chedrese PJ, Kay TWH, Jameson JL. Gonadotropin-releasing hormone stimulates glycoprotein hormone a-subunit messenger ribonucleic acid (mRNA) levels in aT3 cells by increasing transcription and mRNA stability. Endocrinology 1994; 134: 2475–2481.

    Article  PubMed  CAS  Google Scholar 

  45. Clay CM, Keri RA, Finicle AB, Heckert LL, Hamernik DL, Marschke KM, Wilson EM, French FS, Nilson JH. Transcriptional repression of the glycoprotein hormone a subunit gene by androgen may involve direct binding of androgen receptor to the proximal promoter. J Biol Chem 1993; 268:13,556–13,564.

    CAS  Google Scholar 

  46. Keri RA, Andersen B, Kennedy GC, Hamernik DL, Clay CM, Brace AD, Nett TM, Notides AC, Nilson JH. Estradiol inhibits transcription of the human glycoprotein hormone a-subunit gene despite the absence of a high affinity binding site for estrogen receptor. Mol Endocrinol 1991; 5: 725–733.

    Article  PubMed  CAS  Google Scholar 

  47. Attardi B, Klatt B, Little G. Repression of glycoprotein hormone a-subunit gene expression and secretion by activin in aT3–1 cells. Mol Endocrinol 1995; 9: 1737–1749.

    Article  PubMed  CAS  Google Scholar 

  48. Clayton R, Lalloz M, Salton S, Roberts J. Expression of luteinising hormone-ß subunit chloramphenicol acetyltransferase (LH-(3-CAT) fusion gene in rat pituitary cells: induction by cyclic 3’-adenosine monophosphate (cAMP). Mol Cell Endocrinol 1991; 80: 193–202.

    Article  PubMed  CAS  Google Scholar 

  49. Webster JC, Pedersen NR, Edwards DP, Beck CA, Miller WL. The 5’-flanking region of the ovine follicle-stimulating hormone-(3 gene contains six progesterone response elements: three proximal elements are sufficient to increase transcription in the presence of progesterone. Endocrinology 1995; 136: 1049–1058.

    Article  PubMed  CAS  Google Scholar 

  50. Keri RA, Wolfe MW, Saunders TL, Anderson I, Kendall SK, Wagner T, Yeung J, Gorski J, Nett TM, Camper SA, Nilson JH. The proximal promoter of the bovine luteinizing hormone (3-subunit gene confers gonadotrope-specific expression and regulation by gonadotropin-releasing hormone, testosterone, and 17(3-estradiol in transgenic mice. Mol Endocrinol 1994; 8: 1807–1816.

    Article  PubMed  CAS  Google Scholar 

  51. Thomas P, Mellon PL, Turgeon JL, Waring DW. The LßT2 clonal gonadotrope: a model for single cell studies of endocrine cell secretion. Endocrinology 1996; 137: 2979–2989.

    Article  PubMed  CAS  Google Scholar 

  52. Turgeon JL, Windle JJ, Whyte DB, Mellon PL. GnRH and estrogen regulate secretion of LH from an immortal gonadotropin cell line. Progr 76th Annu Meeting Endocrine Soc, Anaheim, CA, p. 646 (abstract), 1994.

    Google Scholar 

  53. Brown P, McNeilly JR, Wallace RM, McNeilly AS, Clark AJ. Characterization of the ovine LH(3subunit gene: the promoter directs gonadotrope-specific expression in transgenic mice. Mol Cell Endocrinol 1993; 93: 157–165.

    Article  PubMed  CAS  Google Scholar 

  54. McNeilly JR, Brown P, Mullins J, Clark AJ, McNeilly AS. Characterization of the ovine LHßsubunit gene: the promoter is regulated by GnRH and gonadal steroids in transgenic mice. J Endocrinol 1996; 151: 481–489.

    Article  PubMed  CAS  Google Scholar 

  55. Fallest PC, Trader GL, Darrow JM, Shupnik MA. Regulation of rat luteinizing hormone 3 gene expression in transgenic mice by steroids and a gonadotropin-releasing hormone antagonist. Mol Endocrinol 1995; 53: 103–109.

    CAS  Google Scholar 

  56. Shupnik MA, Rosenzweig BA. Identification of an estrogen-responsive element in the rat LHf3 gene. J Biol Chem 1991; 266:17,084–17,091.

    CAS  Google Scholar 

  57. Keri RA, Nilson JH. A steroidogenic factor-1 binding site is required for activity of the luteinizing hormone f3 subunit promoter in gonadotropes of transgenic mice. J Biol Chem 1996; 271:10,782–10,785.

    CAS  Google Scholar 

  58. Halvorson LM, Kaiser UB, Chin WW. Stimulation of luteinizing hormone 13 gene promoter activity by the orphan nuclear receptor, steroidogenic factor-1. J Biol Chem 1996; 271: 6645–6650.

    Article  PubMed  CAS  Google Scholar 

  59. Graham K, Low MJ. Hormonal regulation of the human FSH(3 gene in transgenic mice. Prog 4th Intl Pituitary Congress, San Diego, CA, p. F7 (abstract), 1996.

    Google Scholar 

  60. Weiss J, Guendner MJ, Halvorson LM, Jameson JL. Transcriptional activation of the follicle-stimulating hormone (3-subunit gene by activin. Endocrinology 1995; 136: 1885–1891.

    Article  PubMed  CAS  Google Scholar 

  61. Aland E, Windle J, Whyte D, Mellon P. Immortalization of pituitary cells at discrete stages of development by directed oncogenesis in transgenic mice. Development 1996; 122: 3319–3329.

    Google Scholar 

  62. Graham KE, Nusser KD, Low MJ. LßT2 gonadotroph cells secrete follicle stimulating hormone (FSH) in response to activin A. J Endocrinol 1999; 162: R1 - R5.

    Article  PubMed  CAS  Google Scholar 

  63. Kumar TR, Graham KE, Asa SL, Low MJ. Simian Virus 40 T-antigen-induced gonadotroph adenomas: a model of human null cell adenomas. Endocrinology 1998; 139: 3342–3251.

    Article  PubMed  CAS  Google Scholar 

  64. Strahl BD, Huang HJ, Pedersen NR, Wu JC, Ghosh BR, Miller WL. Two proximal activating protein1-binding sites are sufficient to stimulate transcription of the ovine follicle-stimulating hormone-f3 gene. Endocrinology 1997; 138: 2621–2631.

    Article  PubMed  CAS  Google Scholar 

  65. Miller CD, Miller WL. Transcriptional repression of the ovine follicle-stimulating hormone-3 gene by 173-estradiol. Endocrinology 1996; 137: 3437–3446.

    Article  PubMed  CAS  Google Scholar 

  66. Maurer RA, Kim KE. Analysis of gonadotropin gene structure and expression. In: Chin WW, Boime I, eds. Glycoprotein Hormones. Serono Symposia, Norwell, MA, pp. 237–243.

    Google Scholar 

  67. Burrin JM, Jameson JL. Regulation of transfected glycoprotein hormone a-gene expression in primary pituitary cell cultures. Mol Endocrinol 1989; 3: 1643–1651.

    Article  PubMed  CAS  Google Scholar 

  68. Kumar TR, Fairchild-Huntress V, Low MJ. Gonadotrope-specific expression of the human follicle-stimulating hormone 3-subunit gene in pituitaries of transgenic mice. Mol Endocrinol 1992; 6: 81–90.

    Article  PubMed  CAS  Google Scholar 

  69. Kumar TR, Low MJ. Gonadal steroid hormone regulation of human and mouse follicle stimulating hormone 3-subunit gene expression in vivo. Mol Endocrinol 1993; 7: 898–906.

    Article  PubMed  CAS  Google Scholar 

  70. Kumar TR, Low MJ. Hormonal regulation of human follicle-stimulating hormone-3 subunit gene expression: GnRH stimulation and GnRH-independent androgen inhibition. Neuroendocrinology 1995; 61: 628–637.

    Article  PubMed  CAS  Google Scholar 

  71. Gharib SD, Leung PCK, Carroll RS, Chin WW. Androgens positively regulate follicle-stimulating hormone 3-subunit mRNA levels in rat pituitary cells. Mol Endocrinol 1990; 4: 1620–1626.

    Article  PubMed  CAS  Google Scholar 

  72. Markkula M, Kananen K, Paukku T, Männistö A, Loune E, Fröjdman K, Pelliniemi LJ, Huhtaniemi I. Induced ablation of gonadotropins in transgenic mice expressing Herpes simplex virus thymidine kinase under the FSH 3-subunit promoter. Mol Cell Endocrinol 1994; 108: 1–9.

    Article  Google Scholar 

  73. Markkula M, Kananen K, Klemi P, Huhtaniemi I. Pituitary and ovarian expression of the endogenous follicle-stimulating hormone (FSH) subunit genes and an FSH beta-subunit promoter-driven herpes simplex virus thymidine kinase gene in transgenic mice: specific partial ablation of FSH-producing cells by antiherpes treatment. J Endocrinol 1996; 150: 265–273.

    Article  PubMed  CAS  Google Scholar 

  74. Duval DL, Nelson SE, Clay CM. The tripartite basal enhancer of the gonadotropin-releasing hormone (GnRH) receptor gene promoter regulates cell-specific expression through a novel GnRH receptor activating sequence. Mol Endocrinol 1997; 11: 1814–1821.

    Article  PubMed  CAS  Google Scholar 

  75. Albarracin CT, Kaiser UB, Chin WW. Isolation and characterization of the 5’-flanking region of the mouse gonadotropin-releasing hormone receptor gene. Endocrinology 1994; 135: 2300–2306.

    Article  PubMed  CAS  Google Scholar 

  76. Fernandez-Vazquez G, Kaiser UB, Albarracin CT, Chin WW. Transcriptional activation of the gonadotropin-releasing hormone receptor gene by Activin A. Mol Endocrinol 1996; 10: 356–366.

    Article  PubMed  CAS  Google Scholar 

  77. Rawlings SR, Piuz I, Schlegel W, Bockaert J, Journot L. Differential expression of pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptor subtypes in clonal pituitary somatotrophs and gonadotrophs. Endocrinology 1995; 136: 2088–2098.

    Article  PubMed  CAS  Google Scholar 

  78. Garret G, McArdle CA, Hemmings BA, Counis R. Gonadotropin-releasing hormone and pituitary adenylate cyclase-activating polypeptide affect levels of cyclic adenosine 3’, 5’-monophosphatedependent protein kinase A (PKA) subunits in the clonal gonadotrope aT3–1 cells: evidence for cross-talk between PKA and protein kinase C pathways. Endocrinology 1997; 138: 2259–2266.

    Article  Google Scholar 

  79. McArdle CA. Functional interaction between gonadotropin-releasing hormone and PACAP in gonadotropes and aT3–1 cells. Ann NY Acad Sci 1996; 805: 112–121.

    Article  PubMed  CAS  Google Scholar 

  80. Hezerah M. PACAP/VIP receptor subtypes, signal transducers, and effectors in pituitary cells. Ann NY Acad Sci 1996; 805: 315–328.

    Article  Google Scholar 

  81. Wolfe AM, Wray S, Westphal H, Radovick S. Cell-specific expression of the human gonadotropinreleasing hormone gene in transgenic animals. J Biol Chem 1996; 271:20,018–20,023.

    CAS  Google Scholar 

  82. McCue JM, Quirk CC, Nelson SE, Bowen RA, Clay CM. Expression of a murine gonadotropinreleasing hormone receptor-luciferase fusion gene in transgenic mice is diminished by immunoneutralization of gonadotropin-releasing hormone. Endocrinology 1997; 138: 3154–3160.

    Article  PubMed  CAS  Google Scholar 

  83. Lawson MA, Whyte DB, Eraly SA, Mellon PL. Hypothalamus-specific regulation of gonadotropinreleasing hormone gene expression. Recent Prog Horm Res 1995; 50: 459–463.

    PubMed  CAS  Google Scholar 

  84. Wierman ME, Bruder JM, Kepa JK. Regulation of gonadotropin-releasing hormone (GnRH) gene expression in hypothalamic neuronal cells. Cell Mol Neurobiol 1995; 15: 79–88.

    Article  PubMed  CAS  Google Scholar 

  85. Mellon PL, Windle JJ, Goldsmith PC, Padula CA, Roberts JL, Weiner RI Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 1990; 5: 1–10.

    Article  PubMed  CAS  Google Scholar 

  86. Radovick S, Wray S, Muglia L, Westphal H, Olsen B, Smith E, Patriquin E, Wondisford FE. Steroid hormone regulation and tissue-specific expression of the human GnRH gene in cell culture and transgenic animals. Horm Behav 1994; 28: 520–529.

    Article  PubMed  CAS  Google Scholar 

  87. Gore AC, Roberts JL. Regulation of gonadotropin-releasing hormone gene expression in vivo and in vitro. Front Neuroendocrinol 1997; 18: 209–245.

    Article  PubMed  CAS  Google Scholar 

  88. Wetsel WC. Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons: a new tool for dissecting the molecular and cellular basis of LHRH physiology. Cell Mol Neurobiol 1995; 15: 43–78.

    Article  PubMed  CAS  Google Scholar 

  89. 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.

    Article  PubMed  CAS  Google Scholar 

  90. Japon MA, Rubinstein M, Low MJ. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J Histochem Cytochem 1994; 42: 1117–1125.

    Article  PubMed  CAS  Google Scholar 

  91. Sheng H, Zhadanov A, Mosinger B, Fujii T, Bertuzzi S, Grinberg A, Lee E, Huang S, Mahon K, Westphal H. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 1996; 272: 1004–1007.

    Article  PubMed  CAS  Google Scholar 

  92. Bégeot M, Hemming FJ, Dubois PM, Combarnous Y, Dubois MP. Induction of pituitary lactotrope differentiation by luteinizing hormone a subunit. Science 1984; 226: 566–568.

    Article  PubMed  Google Scholar 

  93. Kendall SK, Saunders TL, Jin L, Lloyd RV, Glode LM, Nett TM, Keri RA, Nilson JH, Camper SA. Targeted ablation of pituitary gonadotropes in transgenic mice. Mol Endocrinol 1991; 5: 2025–2036.

    Article  PubMed  CAS  Google Scholar 

  94. Burrows HL, Birkmeier TS, Seasholtz AF, Camper SA. Targeted ablation of cells in the pituitary primordia of transgenic mice. Mol Endocrinol 1996; 10: 1467–1477.

    Article  PubMed  CAS  Google Scholar 

  95. Brinster RL, Chen HY, Trumbauer M. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 1981; 27: 223–231.

    Article  PubMed  CAS  Google Scholar 

  96. Allen RG, Carey C, Parker JD, Mortrud MT, Mellon SH, Low MJ. Targeted ablation of pituitary preroopiomelanocortin cells by Herpes Simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland. Mol Endocrinol 1995; 9: 1005–1016.

    Article  PubMed  CAS  Google Scholar 

  97. Wallace H, Ledent C, Vassart G, Bishop JO, Al-Shawi R. Specific ablation of thyroid follicle cells in adult transgenic mice. Endocrinology 1991; 129: 3217–3226.

    Article  PubMed  CAS  Google Scholar 

  98. Kendall SK, Samuelson LC, Saunders TL, Wood RI, Camper SA. Targeted disruption of the pituitary glycoprotein hormone a-subunit produces hypogonadal and hypothyroid mice. Genes Dev 1995; 9: 2007–2019.

    Article  PubMed  CAS  Google Scholar 

  99. Markkula MA, Hämäläinen TM, Zhang F, Kim KE, Maurer RA, Huhtaniemi IT. The FSH 3-subunit promoter directs the expression of Herpes simplex virus type 1 thymidine kinase to the testis of transgenic mice. Mol Cell Endocrinol 1993; 96: 25–36.

    Article  PubMed  CAS  Google Scholar 

  100. Markkula M, Hämäläinen T, Loune E, Huhtaniemi I. The follicle-stimulating hormone (FSH) 13- and common a-subunits are expressed in mouse testis, as determined in wild-type mice and those transgenic for the FSH (3-subunit/herpes simplex virus thymidine kinase fusion gene. Endocrinology 1995; 136: 4769–4775.

    Article  PubMed  CAS  Google Scholar 

  101. Kumar TR, Wang Y, Lu N, Matzuk MM. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genetics 1997; 15: 201–204.

    Article  CAS  Google Scholar 

  102. Braun RE, Lo D, Pinkert CA, Widera G, Flavell RA, Palmiter RD, Binster RL. Infertility in male transgenic mice: disruption of sperm development by HSV-tk expression in postmeiotic germ cells. Biol Reprod 1990; 43: 684–693.

    Article  PubMed  CAS  Google Scholar 

  103. Schechter J, Stauber C, Windle JJ, Mellon P. Basic fibroblast growth factor: the neurotrophic factor influencing the ingrowth of neural tissue into the anterior pituitary of a-T7 transgenic mice? Neuroendocrinology 1994; 61: 622–627.

    Article  Google Scholar 

  104. Asa SL, Kovacs K, Hammer GD, Liu B, Roos 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.

    Article  PubMed  CAS  Google Scholar 

  105. Asa SL, Kovacs K, Stefaneanu L, Horvath E, Billestrup N, Gonzalez-Manchon C, Vale W. Pituitary mammosomatotroph adenomas develop in old mice transgenic for growth hormone-releasing hormone. Proc Soc Exp Biol Med 1990; 193: 232–235.

    PubMed  CAS  Google Scholar 

  106. Biller BM. Pathogenesis of pituitary Cushing’s syndrome: pituitary versus hypothalamic. Endocrinol Metab Clin North Am 1994; 23: 547–554.

    PubMed  CAS  Google Scholar 

  107. Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W. Development of Cushing’ s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 1992; 130: 3378–3386.

    Article  PubMed  CAS  Google Scholar 

  108. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N, Grandy DK, Low MJ. Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 1997; 19: 103–113.

    Article  PubMed  CAS  Google Scholar 

  109. Saiardi A, Bozzi Y, Baik JH, Borelli E. Antiproliferative role of dopamine: loss of D2 receptors causes hormonal dysfunction and pituitary hyperplasia. Neuron 1997; 19: 115–126.

    Article  PubMed  CAS  Google Scholar 

  110. Risma KA, Clay CM, Nett TM, Wagner R, Yun J, Nilson JH. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci USA 1995; 92: 1322–1326.

    Article  PubMed  CAS  Google Scholar 

  111. Risma KA, Hirshfield AN, Nilson JH. Elevated luteinizing hormone in prepubertal transgenic mice causes hyperandrogenemia, precocious puberty, and substantial ovarian pathology. Endocrinology 1997; 138: 3540–3547.

    Article  PubMed  CAS  Google Scholar 

  112. Neill JD. Sexual differences in the hypothalmic regulation of prolactin secretion. Endocrinology 1972; 90: 1154–1159.

    Article  PubMed  CAS  Google Scholar 

  113. Mason AJ, Pitts SL, Nikolics K, Szonyi E, Wilcox JN, Seeburg PH, Stewart TA. The hypogonadal mouse: reproductive functions restored by gene therapy. Science 1986; 234: 1372–1378.

    Article  PubMed  CAS  Google Scholar 

  114. Kumar T, Low M, Matzuk M. Genetic rescue of follicle stimulating hormone 13-deficient mice. Endocrinology 1998; 139: 3289–3295.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer Science+Business Media New York

About this chapter

Cite this chapter

Graham, K.E., Low, M.J. (2000). Transgenic Approaches to Study Developmental Expression and Regulation of the Gonadotropin Genes. In: Shupnik, M.A. (eds) Gene Engineering in Endocrinology. Contemporary Endocrinology, vol 22. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-221-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-221-0_11

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-147-9

  • Online ISBN: 978-1-59259-221-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics