Skip to main content
SpringerLink
Log in

Role of PITX2 in the Pituitary Gland

  • Chapter
The Molecular Mechanisms of Axenfeld-Rieger Syndrome

Part of the book series: Medical Intelligence Unit ((MIUN))

  • 385 Accesses

Abstract

The pituitary gland is a neuroendocrine organ composed of specialized peptide hormone-producing cells that control many bodily functions. Pituitary development depends on the combined activity of extrinsic signaling molecules and intrinsic transcription factors. One of the earliest acting transcription factors in pituitary development is PITX2, a homeobox transcription factor required for expansion of the pituitary primordium, Rathke’s pouch. Analysis of an allelic series in mice revealed that pituitary gland size and the specification of individual pituitary cell types are also dependent upon Pitx2, and this dependence is sensitive to Pitx2 gene dosage. Mechanistically this pituitary phenotype results from the inability of low levels of PITX2 to activate gene expression of several lineage specific transcription factors, such as Gata2, Sf1 (Nr5a1), Egr1 and Pit1. Our understanding of Pitx2 gene dosage effects on pituitary development suggests a basis for dosage sensitive defects in other organs of Rieger syndrome patients. In addition, analysis of the allelic series in mice raises the possibility of gonadotropin and PIT1 lineage defects in individuals with loss of PITX2 function.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Dubois PM, El Amraoui A. Embryology of the pituitary gland. Trends Endo Metab 1995; 6:1–7.

    Article  CAS  Google Scholar 

  2. Schwind JL. The development of the hypophysis cerebri of the albino rat. Amer J Anat 1928; 41:295–315.

    Article  Google Scholar 

  3. Sheng H, Moriyama K, Yamashita T et al. Multistep control of pituitary organogenesis. Science 1997; 278:1809–1812.

    Article  PubMed  CAS  Google Scholar 

  4. Watanabe YG. Effects of brain and mesenchyme upon the cytogenesis of rat adenohypophysis in vitro. I. Differentiation of adrenocorticotropes. Cell Tissue Res 1982; 227:257–66.

    Article  PubMed  CAS  Google Scholar 

  5. Watanabe YG. An organ culture study on the site of determination of ACTH and LH cells in the rat adenohypophysis. Cell Tiss Res 1982; 227:267–275.

    Article  CAS  Google Scholar 

  6. DuBois PM, Hemming FJF et al. development and regulation of pituitary cell types. J Electron Microscopy Technique 1991; 19:2–20.

    Article  CAS  Google Scholar 

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

    CAS  Google Scholar 

  8. Simmons DM,. Voss JW, Ingraham HA et al. 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.

    PubMed  CAS  Google Scholar 

  9. Burrows HL, Douglas KR, Seasholtz AF et al. Genealogy of the anterior pituitary gland: Tracing a family tree. Trends Endocrin Metab 1999; 10:343–352.

    Article  CAS  Google Scholar 

  10. Dasen JS, Rosenfeld MG. Signaling and transcriptional mechanisms in pituitary development. Annu Rev Neurosci 2001; 24:327–55.

    Article  PubMed  CAS  Google Scholar 

  11. Watkins-Chow DE, Camper SA. How many homeobox genes does it take to make a pituitary gland? Trends in Genetics 1998; 14:284–290.

    Article  PubMed  CAS  Google Scholar 

  12. Gage PJ, Camper SA. Pituitary homeobox 2, a novel member of the bicoid-related family of homeobox genes, is a potential regulator of anterior structure formation. Hum Mol Gen 1997;6:457–464.

    Article  PubMed  CAS  Google Scholar 

  13. Gage PJ, Suh H, Camper SA. Dosage requirement of Pitx2 for development of multiple organs. Development 1999; 126:4643–4651.

    PubMed  CAS  Google Scholar 

  14. Galliot B, de Vargas C, Miller D. Evolution of homeobox genes: Q50 paired-like genes founded the paired class. Dev Genes Evol 1999; 209:186–197.

    Article  PubMed  CAS  Google Scholar 

  15. Quentien MH, Pitoia F, Gunz G et al. Regulation of prolactin, GH, and Pit-1 gene expression in anterior pituitary by Pitx2: An approach using Pitx2 mutants. Endocrinology 2002; 143:2839–51.

    Article  PubMed  CAS  Google Scholar 

  16. Kitamura K, Miura H, Yanazawa M et al. Expression patterns of Brxl (Rieg gene), Sonic hedgehog, Nkx2.2, Dlx1 and Arx during zona limitans intrathalamica and embryonic ventral lateral geniculate nuclear formation. Mech Dev 1997; 67:83–96.

    Article  PubMed  CAS  Google Scholar 

  17. Muccielli ML, Martinez S, Pattyn A et al. Otlx2, an Otx-related homeobox gene expressed in the pituitary gland and in a restricted pattern in the forebrain. Mol Cell Neurosci 1996; 8:258–271.

    Article  PubMed  CAS  Google Scholar 

  18. Suh H, Gage PJ, Drouin J et al. Pitx2 is required at multiple stages of pituitary organogenesis: Pituitary primordium formation and cell specification. Development 2002; 12:329–37.

    Google Scholar 

  19. Gage PJ, Roller ML, Saunders TL et al. Anterior pituitary cells defective in the cell autonomous factor, df, undergo cell lineage specification but not expansion. Development 1996; 122:151–160.

    PubMed  CAS  Google Scholar 

  20. Li S, Crenshaw EB, Rawson EJ et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene Pit-1. Nature 1990; 347:528–533.

    Article  PubMed  CAS  Google Scholar 

  21. Bodner M, Castrillo J-L, Theill LE et al. The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein. Cell 1988; 55:505–518.

    Article  PubMed  CAS  Google Scholar 

  22. Gordon DF, Haugen BR, Sarapura VD et al. Analysis of Pit-1 in regulating mouse TSHβ promoter activity in thyrotropes. Mol Cell Endocrinology 1993; 96:75–84.

    Article  CAS  Google Scholar 

  23. Gordon DF, Lewis SR, Haugen BR et al. Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin β-subunit promoter. J Biol Chem 1997; 272:24339–24347.

    Article  PubMed  CAS  Google Scholar 

  24. Ingraham HA, Chen R, Mangalam HJ et al. A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 1988; 55:519–529.

    Article  PubMed  CAS  Google Scholar 

  25. Kitamura K, Miura K, Miyagawa-Tomita S. Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra-and periocular mesoderm and right pulmonary isomerism. Development 1999; 126:5749–5758.

    PubMed  CAS  Google Scholar 

  26. Lin CR, Kioussi C, O’Connell S et al. Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis. Nature 1999; 401:279–282.

    Article  PubMed  CAS  Google Scholar 

  27. Lu M-F, Pressman C, Dyer R et al. Function of Rieger syndrome gene in left-right asymmetry and craniofacial development. Nature 1999; 401:276–278.

    Article  PubMed  CAS  Google Scholar 

  28. Dattani MT, Martinez-Barbera JP, Thomas PQ et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nature Genetics 1998; 19:125–133.

    Article  PubMed  CAS  Google Scholar 

  29. Thomas PQ, Dattani MT, Brickman JM et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10:39–45.

    Article  PubMed  CAS  Google Scholar 

  30. Luo X, Ikeda Y, Parker KL. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 1994; 77:481–490.

    Article  PubMed  CAS  Google Scholar 

  31. Topilko P, Schneider-Maunoury S, Levi G et al. Multiple pituitary and ovarian defects in Krox-24 (NGF1-A, Egr-1)-targeted mice. Mol Endo 1998; 12:107–122.

    Article  CAS  Google Scholar 

  32. Camper SA, Saunders TL, Katz RW et al. The Pit-1 transcription factor gene is a candidate for the Snell dwarf mutation. Genomics 1990; 8:586–590.

    Article  PubMed  CAS  Google Scholar 

  33. Arakawa H, Nakamura T, Zhadanov AB et al. Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene. Proc Natl Acad Sci USA 1998;95:4573–4578.

    Article  PubMed  CAS  Google Scholar 

  34. Kurotani R, Tahara S, Sanno N et al. Expression of Ptx1 in the adult rat pituitary glands and pituitary cell lines: Hormone-secreting cells and folliculo-stellate cells. Cell Tissue Res 1999;298:55–61.

    Article  CAS  Google Scholar 

  35. Lanctot C, Moreau A, Chamberland M et al. Hindlimb patterning and mandible development require the Ptx1 gene. Development 1999; 126:1805–1810.

    PubMed  CAS  Google Scholar 

  36. Szeto DP, Rodriquez-Estaban C, Ryan AK et al. Role of Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev 1999; 13:484–494.

    PubMed  CAS  Google Scholar 

  37. Bach I, Rhodes SJ, Pearse RV et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc Nat Acad Sci USA 1995;92:2720–2724.

    Article  PubMed  CAS  Google Scholar 

  38. Sheng HZ, Zhadanov AB, Mosinger B et al. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 1996; 272:1004–1007.

    Article  PubMed  CAS  Google Scholar 

  39. Raetzman LT, Ward R, Camper SA. Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia. Development 129:4229–39.

    Google Scholar 

  40. Netchine I, Sobrier ML, Krude H et al. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nature Genetics 2000; 25:182–186.

    Article  PubMed  CAS  Google Scholar 

  41. Machinis K, Pantel J, Netchine I et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001; 69:961–968.

    Article  PubMed  CAS  Google Scholar 

  42. Mellon PL, Windle JJ, Weiner RI. Immortalization of neuroendocrine cells by targeted oncogenesis. Recent Prog Horm Res 1991; 47:69–93.

    PubMed  CAS  Google Scholar 

  43. Tremblay JJ, Lanctot C, Drouin J. The pan-pituitary activator of transcription, Ptx1 (Pituitary Homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3. Mol Endo 1998; 12:428–441.

    Article  CAS  Google Scholar 

  44. Tremblay JJ, Drouin J. Egr-1 is a downstream effector of GnRH and synergizes by direct interaction with Ptx1 and SF-1 to enhance luteinizing hormone beta gene transcription. Mol Cell Biol 1999; 1:2567–76.

    Google Scholar 

  45. Tremblay JJ, Marcil A, Gauthier Y et al. Ptx1 regulates Sf-1 activity by an interaction that mimics the role of the ligand-binding domain. EMBO J 1999; 18:3431–3441.

    Article  PubMed  CAS  Google Scholar 

  46. Tremblay JJ, Goodyer CG, Drouin J. Transcriptional properties of Ptx1 and Ptx2 isoforms. Neu-roendocrinology 2000; 71:277–86.

    CAS  Google Scholar 

  47. Amendt B, Sutherland L, Semina E et al. The molecular basis of Rieger syndrome: Analysis of Pitx2 homeodomain protein activities. J Biol Chem 1998; 273:20066–20072.

    Article  PubMed  CAS  Google Scholar 

  48. Cox CJ, Espinoza HM, McWilliams B et al. Differential regulation of gene expression by PITX2 isoforms. J Biol Chem 2002; 277:25001–25010.

    Article  PubMed  CAS  Google Scholar 

  49. Saadi I, Semina EV, Amendt BA et al. Identification of a dominant negative homeodomain mutation in Rieger syndrome. J Biol Chem 2001; 276:23034–23041.

    Article  PubMed  CAS  Google Scholar 

  50. Darwin C. Animals and plants under domestication. NY: D. Appleton & Co., 1893:434–461.

    Google Scholar 

  51. Vossius A. Kongenitale anomalien der iris. Klin Mbl Augenheilk 1883; 21:233–237.

    Google Scholar 

  52. Rieger H. Bieträge zur kenntnis seltener missbindungen der iris. Albrecht von Graefes Arch Klin Opthalmol 1935; 133:602.

    Article  Google Scholar 

  53. Fitch N, Kaback M. The Axenfeld syndrome and the Rieger syndrome. J Med Genet 1978; 15:30–34.

    Article  PubMed  CAS  Google Scholar 

  54. Shields MB, Buckley E, Klintworth GK et al. Axenfeld-Rieger syndrome. A spectrum of develop mental disorders. Surv Ophthalmol 1985; 29:387–409.

    Article  PubMed  CAS  Google Scholar 

  55. Mears AJ, Jordan T, Mirzayans F et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Gen 1998; 63:1316–28.

    Article  CAS  Google Scholar 

  56. Semina EV, Reiter R, Leysens NJ et al. Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nature Genetics 1996; 14:392–399.

    Article  PubMed  CAS  Google Scholar 

  57. Feingold M, Shiere F, Fogels HR et al. Rieger’s syndrome. Pediatrics 1969; 44:564.

    PubMed  CAS  Google Scholar 

  58. Sadeghi-Nejad A, Senior B. A familial syndrome of isolated “aplasia” of the anterior pituitary. J Pediatrics 1974; 84:79–84.

    Article  CAS  Google Scholar 

  59. Aarskog D, Ose L, Pande H et al. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes. Am J Med Genet 1983; 15:29–38.

    Article  PubMed  CAS  Google Scholar 

  60. Kleinmann RE, Kazarian EL, Raptopoulos V et al. Primary empty sella and Rieger’s anomaly of the anterior chamber of the eye: A familial syndrome. N Engl J Med 1981; 304:90–93.

    Article  PubMed  CAS  Google Scholar 

  61. Amendt BA, Semina EV, Alward WL. Rieger syndrome: A clinical, molecular, and biochemical analysis. Cell Mol Life Sci 2000; 57:1652–1666.

    Article  PubMed  CAS  Google Scholar 

  62. Doward W, Perveen R, Lloyd IC et al. A mutation in the RIEG1 gene associated with Peters’ anomaly. J Med Genet 1999; 36:152–155.

    PubMed  CAS  Google Scholar 

  63. Kulak SC, Kozlowski K, Semina EV et al. Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome. Hum Mol Genet 1998; 7:1113–1117.

    Article  PubMed  CAS  Google Scholar 

  64. Perveen R, Lloyd IC, Clayton-Smith J et al. Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Invest Ophthalmol Vis Sci 2000; 41:2456–2460.

    PubMed  CAS  Google Scholar 

  65. Priston M, Kozlowski K, Gill D et al. Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome. Hum Mol Genet 2001;10:1631–1638.

    Article  PubMed  CAS  Google Scholar 

  66. Bitoun P, Machinis K, Semina E et al. Heterozygous PITX2/RIEG1 gene deletion associated with GH deficiency in Rieger syndrome. Am J Hum Gen 2001; (Suppl): Abstract 2525.

    Google Scholar 

  67. Kozlowski K, Walter MA. Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. Hum Mol Genet 2000; 9:2131–2139.

    Article  PubMed  CAS  Google Scholar 

  68. Lines MA, Kozlowski K, Walter MA. Molecular Genetics of Axenfeld-Rieger malformations. Hum Mol Genet 2002; 11:1177–87.

    Article  PubMed  CAS  Google Scholar 

  69. Camper SA, Suh H, Raetzman L et al. Pituitary gland development. Mouse development. In: Rossant J, Tarn P, eds. NY: Academic Press, 2002:499–518.

    Google Scholar 

  70. Cogan JD, Wu W, Phillips JA et al. The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J Clin Endo Metab 1998; 83:3346–3349.

    Article  CAS  Google Scholar 

  71. Sornson MW, Wu W, Dasen JS et al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 1996; 384:327–333.

    Article  PubMed  CAS  Google Scholar 

  72. Gage PJ, Brinkmeier ML, Scarlett LM et al. The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage specific cell proliferation. Mol Endo 1996; 10:1570–1581.

    Article  CAS  Google Scholar 

  73. Tang K, Bartke A, Gardiner CS et al. Gonadotropin secretion, synthesis, and gene expression in human growth hormone transgenic mice and in Ames dwarf mice. Endocrinology 1993;132:2518–2524.

    Article  PubMed  CAS  Google Scholar 

  74. Tatsumi K, Miyai K, Notomi T. Cretinism with combined hormone deficiency caused by a mutation in the Pit-1 gene. Nature Genetics 1992; 1:56.

    Article  PubMed  CAS  Google Scholar 

  75. Dasen JS, O’Connell SM, Flynn SE et al. Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types. Cell 1999; 97:587–598.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Hoonkyo Suh, Donna M. Martin, Michael A. Charles, Igor O. Nasonkin, Philip J. Gage & Sally A. Camper

Authors
  1. Hoonkyo Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donna M. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. Charles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Igor O. Nasonkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip J. Gage
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sally A. Camper
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Eurekah.com and Springer Science+Business Media

About this chapter

Cite this chapter

Suh, H., Martin, D.M., Charles, M.A., Nasonkin, I.O., Gage, P.J., Camper, S.A. (2005). Role of PITX2 in the Pituitary Gland. In: The Molecular Mechanisms of Axenfeld-Rieger Syndrome. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-28672-1_5

Download citation

Publish with us

Policies and ethics

Search

Navigation