Abstract
The anterior pituitary gland secretes hormones that regulate developmental and physiological processes, including growth, the stress response, metabolic status, reproduction and lactation. During embryogenesis, cellular determination and differentiation events establish specialized hormone-secreting cell types within the anterior pituitary gland. These developmental decisions are mediated in part by the actions of a cascade of transcription factors, many of which belong to the homeodomain class of DNA-binding proteins. The discovery of some of these regulatory proteins has facilitated genetic analyses of patients with hormone deficiencies. The findings of these studies reveal that congenital defects—ranging from isolated hormone deficiencies to combined pituitary hormone deficiency syndromes—are sometimes associated with mutations in the genes encoding pituitary-acting developmental transcription factors. The phenotypes of affected individuals and animal models have together provided useful insights into the biology of these transcription factors and have suggested new hypotheses for testing in the basic science laboratory. Here, we summarize the gene regulatory pathways that control anterior pituitary development, with emphasis on the role of the homeodomain transcription factors in normal pituitary organogenesis and heritable pituitary disease.
Key Points
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Investigating the molecular biology of pituitary development has allowed translation of research findings into the clinic and subsequent reciprocal transfer of information back from patients to the basic science laboratory
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Many regulatory genes involved in pituitary development have been characterized; however, the etiology of most cases of combined pituitary hormone deficiency (CPHD) remains unknown
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Septo-optic dysplasia is a relatively common cause of CPHD, but rarely involves mutations in the gene encoding the homeodomain transcription factor HESX1
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All mutations identified in the genes of pituitary-acting homeodomain transcription factors are associated with variable phenotypes, which makes strict genotype–phenotype correlations challenging
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Patients with CPHD are at risk of developing additional hormone deficiencies over time; therefore, careful follow-up and long-term testing is critical
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When disease-related mutations are identified, genetic counseling can be useful to predict which additional hormone deficiencies may develop, as well as to evaluate the potential risk for future children
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References
Alatzoglou, K. S. & Dattani, M. T. Genetic causes and treatment of isolated growth hormone deficiency—an update. Nat. Rev. Endocrinol. 6, 562–576 (2010).
Davis, S. W. et al. Molecular mechanisms of pituitary organogenesis: In search of novel regulatory genes. Mol. Cell Endocrinol. 323, 4–19 (2010).
Kelberman, D. & Dattani, M. T. The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism. Ann. Med. 38, 560–577 (2006).
Kelberman, D., Rizzoti, K., Lovell-Badge, R., Robinson, I. C. & Dattani, M. T. Genetic regulation of pituitary gland development in human and mouse. Endocr. Rev. 30, 790–829 (2009).
Romero, C. J., Nesi-França, S. & Radovick, S. The molecular basis of hypopituitarism. Trends Endocrinol. Metab. 20, 506–516 (2009).
Zhu, X., Gleiberman, A. S. & Rosenfeld, M. G. Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol. Rev. 87, 933–963 (2007).
Vallette-Kasic, S. et al. Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT mutations. J. Clin. Endocrinol. Metabol. 90, 1323–1331 (2005).
Bell, J. et al. Long-term safety of recombinant human growth hormone in children. J. Clin. Endocrinol. Metab. 95, 167–177 (2010).
Phillips, J. 3rd, Vnencak-Jones, C. & Layman, L. PROP1-related combined pituitary hormone deficiency (CPHD). Gene Reviews at Gene Tests: Medical Genetics Information Resource [online], (2005).
Toogood, A. A. & Stewart, P. M. Hypopituitarism: clinical features, diagnosis, and management. Endocrinol. Metab. Clin. North Am. 37, 235–261 (2008).
Walvoord, E. Sex steroid replacement for induction of puberty in multiple pituitary hormone deficiency. Pediatr. Endocrinol. Rev. 6 (Suppl. 2), 298–305 (2009).
Richmond, E. J. & Rogol, A. D. Male pubertal development and the role of androgen therapy. Nat. Clin. Pract. Endocrinol. Metab. 3, 338–344 (2007).
Deladoëy, J. et al. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 84, 1645–1650 (1999).
Mehta, A. et al. Congenital hypopituitarism: clinical, molecular and neuroradiological correlates. Clin. Endocrinol. (Oxf.) 71, 376–382 (2009).
Turton, J. P. et al. Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD). Clin. Endocrinol. (Oxf.) 63, 10–18 (2005).
Turton, J. P. et al. Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 90, 4762–4770 (2005).
de Graaff, L. C. et al. PROP1, HESX1, POU1F1, LHX3 and LHX4 mutation and deletion screening and GH1 P89L and IVS3+1/+2 mutation screening in a Dutch nationwide cohort of patients with combined pituitary hormone deficiency. Horm. Res. Paediatr. 73, 363–371 (2010).
Patel, L., McNally, R. J., Harrison, E., Lloyd, I. C. & Clayton, P. E. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J. Pediatr. 148, 85–88 (2006).
Hoyt, W. F., Kaplan, S. L., Grumbach, M. M. & Glaser, J. S. Septo-optic dysplasia and pituitary dwarfism. Lancet 1, 893–894 (1970).
Roessmann, U. Septo-optic dysplasia (SOD) or DeMorsier syndrome. J. Clin. Neuroophthalmol. 9, 156–159 (1989).
Birkebaek, N. H. et al. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J. Clin. Endocrinol. Metab. 88, 5281–5286 (2003).
Cameron, F. J., Khadilkar, V. V. & Stanhope, R. Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum. Eur. J. Pediatr. 158, 97–102 (1999).
Alatzoglou, K. S. & Dattani, M. T. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum. Dev. 85, 705–712 (2009).
Dasen, J. S. et al. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 15, 3193–3207 (2001).
Ericson, J., Norlin, S., Jessell, T. M. & Edlund, T. Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 125, 1005–1015 (1998).
Potok, M. A. et al. WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth. Dev. Dyn. 237, 1006–1020 (2008).
Treier, M. et al. Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev. 12, 1691–1704 (1998).
Treier, M. et al. Hedgehog signaling is required for pituitary gland development. Development 128, 377–386 (2001).
Hermesz, E., Mackem, S. & Mahon, K. A. Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. Development 122, 41–52 (1996).
Thomas, P. & Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496 (1996).
Gleiberman, A. S. et al. Genetic approaches identify adult pituitary stem cells. Proc. Natl Acad. Sci. USA 105, 6332–6337 (2008).
Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).
Fauquier, T., Rizzoti, K., Dattani, M., Lovell-Badge, R. & Robinson, I. C. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc. Natl Acad. Sci. USA 105, 2907–2912 (2008).
Kelberman, D. et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J. Clin. Invest. 116, 2442–2455 (2006).
Japón, M. A., Rubinstein, M. & Low, M. J. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J. Histochem. Cytochem. 42, 1117–1125 (1994).
Simmons, D. M. et al. Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev. 4, 695–711 (1990).
Dubois, P. M., el Amraoui, A. & Héritier, A. G. Development and differentiation of pituitary cells. Microsc. Res. Tech. 39, 98–113 (1997).
Ingraham, H. A. et al. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev. 8, 2302–2312 (1994).
Li, S. et al. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 347, 528–533 (1990).
Lamolet, B. et al. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104, 849–859 (2001).
Dattani, M. T. et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat. Genet. 19, 125–133 (1998).
Olson, L. E. et al. Homeodomain-mediated β-catenin-dependent switching events dictate cell-lineage determination. Cell 125, 593–605 (2006).
Andoniadou, C. L. et al. Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development 134, 1499–1508 (2007).
Kelberman, D. & Dattani, M. T. Septo-optic dysplasia—novel insights into the aetiology. Horm. Res. 69, 257–265 (2008).
McNay, D. E. et al. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J. Clin. Endocrinol. Metab. 92, 691–697 (2007).
Thomas, P. Q. et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum. Mol. Genet. 10, 39–45 (2001).
Sobrier, M. L. et al. Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities. J. Clin. Endocrinol. Metab. 91, 4528–4536 (2006).
Castinetti, F. et al. A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J. Clin. Endocrinol. Metab. 93, 2790–2799 (2008).
Tajima, T. et al. A novel missense mutation (P366T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr. J. 54, 637–641 (2007).
Tajima, T. et al. OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J. Clin. Endocrinol. Metab. 94, 314–319 (2009).
Sajedi, E. et al. Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Dis. Model Mech. 1, 241–254 (2008).
Murray, P. G., Paterson, W. F. & Donaldson, M. D. Maternal age in patients with septo-optic dysplasia. J. Pediatr. Endocrinol. Metab. 18, 471–476 (2005).
Riedl, S. et al. Refining clinical phenotypes in septo-optic dysplasia based on MRI findings. Eur. J. Pediatr. 167, 1269–1276 (2008).
Stevens, C. A. & Dobyns, W. B. Septo-optic dysplasia and amniotic bands: further evidence for a vascular pathogenesis. Am. J. Med. Genet. A 125A, 12–16 (2004).
Hunter, C. S. & Rhodes, S. J. LIM-homeodomain genes in mammalian development and human disease. Mol. Biol. Rep. 32, 67–77 (2005).
Sheng, H. Z. et al. Multistep control of pituitary organogenesis. Science 278, 1809–1812 (1997).
Takuma, N. et al. Formation of Rathke's pouch requires dual induction from the diencephalon. Development 125, 4835–4840 (1998).
Thaler, J. P. et al. A postmitotic role for Isl-class LIM homeodomain proteins in the assignment of visceral spinal motor neuron identity. Neuron 41, 337–350 (2004).
Shimomura, H. et al. Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49, 1597–1600 (2000).
Roberson, M. S., Schoderbek, W. E., Tremml, G. & Maurer, R. A. Activation of the glycoprotein hormone alpha-subunit promoter by a LIM-homeodomain transcription factor. Mol. Cell Biol. 14, 2985–2993 (1994).
Zhao, Y., Mailloux, C. M., Hermesz, E., Palkóvits, M. & Westphal, H. A role of the LIM-homeobox gene Lhx2 in the regulation of pituitary development. Dev. Biol. 337, 313–323 (2010).
Sheng, H. Z. et al. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272, 1004–1007 (1996).
Bach, I. et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc. Natl Acad. Sci. USA 92, 2720–2724 (1995).
Seidah, N. G. et al. The mouse homeoprotein mLIM-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary. DNA Cell Biol. 13, 1163–1180 (1994).
Sobrier, M. L. et al. Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development. Gene Expr. Patterns 5, 279–284 (2004).
Chou, S. J. et al. Conserved regulatory elements establish the dynamic expression of Rpx/HesxI in early vertebrate development. Dev. Biol. 292, 533–545 (2006).
Ellsworth, B. S., Butts, D. L. & Camper, S. A. Mechanisms underlying pituitary hypoplasia and failed cell specification in Lhx3-deficient mice. Dev. Biol. 313, 118–129 (2008).
Granger, A. et al. The LIM-homeodomain proteins Isl-1 and Lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter. Mol. Endocrinol. 20, 2093–2108 (2006).
McGillivray, S. M., Bailey, J. S., Ramezani, R., Kirkwood, B. J. & Mellon, P. L. Mouse GnRH receptor gene expression is mediated by the LHX3 homeodomain protein. Endocrinology 146, 2180–2185 (2005).
Sloop, K. W. et al. Differential activation of pituitary hormone genes by human Lhx3 isoforms with distinct DNA binding properties. Mol. Endocrinol. 13, 2212–2225 (1999).
Colvin, S. C., Mullen, R. D., Pfaeffle, R. W. & Rhodes, S. J. LHX3 and LHX4 transcription factors in pituitary development and disease. Pediatr. Endocrinol. Rev. 6 (Suppl. 2), 283–290 (2009).
Bhangoo, A. P. et al. Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J. Clin. Endocrinol. Metab. 91, 747–753 (2006).
Bonfig, W., Krude, H. & Schmidt, H. A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature. Eur. J. Pediatr. doi:10.1007/s004310111393-x.
Kriström, B. et al. A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations. J. Clin. Endocrinol. Metab. 94, 1154–1161 (2009).
Netchine, I. et al. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat. Genet. 25, 182–186 (2000).
Pfaeffle, R. W. et al. Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J. Clin. Endocrinol. Metab. 92, 1909–1919 (2007).
Rajab, A. et al. Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum. Mol. Genet. 17, 2150–2159 (2008).
Colvin, S. C., Malik, R. E., Showalter, A. D., Sloop, K. W. & Rhodes, S. J. Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo. Proc. Natl Acad. Sci. USA 108, 173–178 (2011).
Li, H. et al. Gsh-4 encodes a LIM-type homeodomain, is expressed in the developing central nervous system and is required for early postnatal survival. EMBO J. 13, 2876–2885 (1994).
Sharma, K. et al. LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell 95, 817–828 (1998).
Dateki, S. et al. Mutation and gene copy number analyses of six pituitary transcription factor genes in 71 patients with combined pituitary hormone deficiency: identification of a single patient with LHX4 deletion. J. Clin. Endocrinol. Metab. 95, 4043–4047 (2010).
Machinis, K. et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am. J. Hum. Genet. 69, 961–968 (2001).
Pfaeffle, R. W. et al. Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J. Clin. Endocrinol. Metab. 93, 1062–1071 (2008).
Tajima, T., Yorifuji, T., Ishizu, K. & Fujieda, K. A novel mutation (V101A) of the LHX4 gene in a Japanese patient with combined pituitary hormone deficiency. Exp. Clin. Endocrinol. Diabetes 118, 405–409 (2010).
Simeone, A. et al. A vertebrate gene related to orthodenticle contains a homeodomain of the bicoid class and demarcates anterior neuroectoderm in the gastrulating mouse embryo. EMBO J. 12, 2735–2747 (1993).
Ang, S. L., Conlon, R. A., Jin, O. & Rossant, J. Positive and negative signals from mesoderm regulate the expression of mouse Otx2 in ectoderm explants. Development 120, 2979–2989 (1994).
Ang, S. L. et al. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 122, 243–252 (1996).
Martinez-Morales, J. R., Signore, M., Acampora, D., Simeone, A. & Bovolenta, P. Otx genes are required for tissue specification in the developing eye. Development 128, 2019–2030 (2001).
Kurokawa, D. et al. Regulation of Otx2 expression and its functions in mouse epiblast and anterior neuroectoderm. Development 131, 3307–3317 (2004).
Dateki, S. et al. OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. J. Clin. Endocrinol. Metab. 93, 3697–3702 (2008).
Diaczok, D., Romero, C., Zunich, J., Marshall, I. & Radovick, S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 93, 4351–4359 (2008).
Ragge, N. K. et al. Heterozygous mutations of OTX2 cause severe ocular malformations. Am. J. Hum. Genet. 76, 1008–1022 (2005).
Bodner, M. et al. The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein. Cell 55, 505–518 (1988).
Ingraham, H. A. et al. A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell 55, 519–529 (1988).
Jacobson, E. M., Li, P., Leon-del-Rio, A., Rosenfeld, M. G. & Aggarwal, A. K. Structure of Pit-1 POU domain bound to DNA as a dimer: unexpected arrangement and flexibility. Genes Dev. 11, 198–212 (1997).
Scully, K. M. et al. Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification. Science 290, 1127–1131 (2000).
Ohta, K. et al. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem. Biophys. Res. Commun. 189, 851–855 (1992).
Pfäffle, R. W. et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 257, 1118–1121 (1992).
Radovick, S. et al. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 257, 1115–1118 (1992).
Tatsumi, K. et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat. Genet. 1, 56–58 (1992).
Szeto, D. P. et al. Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 13, 484–494 (1999).
Gage, P. J., Suh, H. & Camper, S. A. Dosage requirement of Pitx2 for development of multiple organs. Development 126, 4643–4651 (1999).
Suh, H., Gage, P. J., Drouin, J. & Camper, S. A. Pitx2 is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification. Development 129, 329–337 (2002).
Charles, M. A. et al. PITX genes are required for cell survival and Lhx3 activation. Mol. Endocrinol. 19, 1893–1903 (2005).
Saadi, I. et al. Identification of a dominant negative homeodomain mutation in Rieger syndrome. J. Biol. Chem. 276, 23034–23041 (2001).
Idrees, F. et al. A novel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 184–191 (2006).
Meyer-Marcotty, P., Weisschuh, N., Dressler, P., Hartmann, J. & Stellzig-Eisenhauer, A. Morphology of the sella turcica in Axenfeld-Rieger syndrome with PITX2 mutation. J. Oral Pathol. Med. 37, 504–510 (2008).
Tümer, Z. & Bach-Holm, D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. Eur. J. Hum. Genet. 17, 1527–1539 (2009).
Vieira, V. et al. Identification of four new PITX2 gene mutations in patients with Axenfeld-Rieger syndrome. Mol. Vis. 12, 1448–1460 (2006).
Gage, P. J. 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. Endocrinol. 10, 1570–1581 (1996).
Sornson, M. W. et al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384, 327–333 (1996).
Andersen, B. et al. The Ames dwarf gene is required for Pit-1 gene activation. Dev. Biol. 172, 495–503 (1995).
Cogan, J. D. et al. The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 83, 3346–3349 (1998).
Mody, S., Brown, M. R. & Parks, J. S. The spectrum of hypopituitarism caused by PROP1 mutations. Best Pract. Res. Clin. Endocrinol. Metab. 16, 421–431 (2002).
Reynaud, R. et al. Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. J. Clin. Endocrinol. Metab. 91, 3329–3336 (2006).
Vieira, T. C., Boldarine, V. T. & Abucham, J. Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency. Arq Bras. Endocrinol. Metabol. 51, 1097–1103 (2007).
Flück, C. et al. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg→Cys at codon 120 (R120C). J. Clin. Endocrinol. Metab. 83, 3727–3734 (1998).
Mendonca, B. B. et al. Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301, G302 in the PROP1 gene. J. Clin. Endocrinol. Metab. 84, 942–945 (1999).
Agarwal, G., Bhatia, V., Cook, S. & Thomas, P. Q. Adrenocorticotropin deficiency in combined pituitary hormone deficiency patients homozygous for a novel PROP1 deletion. J. Clin. Endocrinol. Metab. 85, 4556–4561 (2000).
Böttner, A. et al. PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J. Clin. Endocrinol. Metab. 89, 5256–5265 (2004).
Fofanova, O. V. et al. A mutational hot spot in the Prop-1 gene in Russian children with combined pituitary hormone deficiency. Pituitary 1, 45–49 (1998).
Kelberman, D. et al. Molecular analysis of novel PROP1 mutations associated with combined pituitary hormone deficiency (CPHD). Clin. Endocrinol. (Oxf.) 70, 96–103 (2009).
Zhang, H., Wang, Y., Han, L., Gu, X. & Shi, D. A large deletion of PROP1gene in patients with combined pituitary hormone deficiency from two unrelated Chinese pedigrees. Horm. Res. Paediatr. 74, 98–105 (2010).
Vieira, T. C. et al. Familial combined pituitary hormone deficiency due to a novel mutation R99Q in the hot spot region of Prophet of Pit-1 presenting as constitutional growth delay. J. Clin. Endocrinol. Metab. 88, 38–44 (2003).
Riepe, F. G. et al. Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation. J. Clin. Endocrinol. Metab. 86, 4353–4357 (2001).
Asteria, C., Oliveira, J. H., Abucham, J. & Beck-Peccoz, P. Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene. Eur. J. Endocrinol. 143, 347–352 (2000).
Lazar, L., Gat-Yablonski, G., Kornreich, L., Pertzelan, A. & Phillip, M. PROP-1 gene mutation (R120C) causing combined pituitary hormone deficiencies with variable clinical course in eight siblings of one Jewish Moroccan family. Horm. Res. 60, 227–231 (2003).
Maghnie, M., Ghirardello, S. & Genovese, E. Magnetic resonance imaging of the hypothalamus–pituitary unit in children suspected of hypopituitarism: who, how and when to investigate. J. Endocrinol. Invest. 27, 496–509 (2004).
Voutetakis, A. et al. Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate with a novel Prop1 gene mutation (Q83X). Eur. J. Endocrinol. 150, 257–264 (2004).
Nascif, S. O., Vieira, T. C., Ramos-Dias, J. C., Lengyel, A. M. & Abucham, J. Waxing and waning of a pituitary mass in a young woman with combined pituitary hormone deficiency (CPHD) due to a PROP-1 mutation. Pituitary 9, 47–52 (2006).
Ward, R. D. et al. Role of PROP1 in pituitary gland growth. Mol. Endocrinol. 19, 698–710 (2005).
Brinkmeier, M. L. et al. Discovery of transcriptional regulators and signaling pathways in the developing pituitary gland by bioinformatic and genomic approaches. Genomics 93, 449–460 (2009).
Ben-Jonathan, N., LaPensee, C. R. & LaPensee, E. W. What can we learn from rodents about prolactin in humans? Endocr. Rev. 29, 1–41 (2008).
Soares, M. J. The prolactin and growth hormone families: pregnancy-specific hormones/cytokines at the maternal-fetal interface. Reprod. Biol. Endocrinol. 2, 51 (2004).
Dewan, A. et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989–992 (2006).
Gurnett, C. A. et al. Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am. J. Med. Genet. A 143, 27–32 (2007).
Ohno, K., Sadeh, M., Blatt, I., Brengman, J. M. & Engel, A. G. E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome. Hum. Mol. Genet. 12, 739–748 (2003).
Emison, E. S. et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434, 857–863 (2005).
He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522–531 (2004).
Zhang, Z., Florez, S., Gutierrez-Hartmann, A., Martin, J. F. & Amendt, B. A. MicroRNAs regulate pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor 1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression. J. Biol. Chem. 285, 34718–34728 (2010).
Scheithauer, B. W. et al. The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin. Proc. 65, 461–474 (1990).
Vankelecom, H. Pituitary stem/progenitor cells: embryonic players in the adult gland? Eur. J. Neurosci. 32, 2063–2081 (2010).
Chen, J. et al. Pituitary progenitor cells tracked down by side population dissection. Stem Cells 27, 1182–1195 (2009).
Chen, J. et al. The adult pituitary contains a cell population displaying stem/progenitor cell and early embryonic characteristics. Endocrinology 146, 3985–3998 (2005).
Galichet, C., Lovell-Badge, R. & Rizzoti, K. Nestin-Cre mice are affected by hypopituitarism, which is not due to significant activity of the transgene in the pituitary gland. Plos ONE 5, e11443 (2010).
Garcia-Lavandeira, M. et al. A GRFa2/Prop1/stem (GPS) cell niche in the pituitary. Plos ONE 4, e4815 (2009).
Nasonkin, I. O. et al. Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice. Hum. Mol. Genet. 13, 2727–2735 (2004).
Bonnefont, X. et al. Revealing the large-scale network organization of growth hormone-secreting cells. Proc. Natl Acad. Sci. USA 102, 16880–16885 (2005).
Chauvet, N. et al. Characterization of adherens junction protein expression and localization in pituitary cell networks. J. Endocrinol. 202, 375–387 (2009).
Elliott, J., Maltby, E. L. & Reynolds, B. A case of deletion 14(q22.1→q22.3) associated with anophthalmia and pituitary abnormalities. J. Med. Genet. 30, 251–252 (1993).
Wu, W. et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat. Genet. 18, 147–149 (1998).
Alarid, E. T., Windle, J. J., Whyte, D. B. & Mellon, P. L. Immortalization of pituitary cells at discrete stages of development by directed oncogenesis in transgenic mice. Development 122, 3319–3329 (1996).
Sizova, D., Ho, Y., Cooke, N. E. & Liebhaber, S. A. Research resource: T-antigen transformation of pituitary cells captures three novel cell lines in the Pit-1 lineage. Mol. Endocrinol. 24, 2232–2240 (2010).
Liu, J. et al. Tbx19, a tissue-selective regulator of POMC gene expression. Proc. Natl Acad. Sci. USA 98, 8674–8679 (2001).
Demarco, I. A., Voss, T. C., Booker, C. F. & Day, R. N. Dynamic interactions between Pit-1 and C/EBPalpha in the pituitary cell nucleus. Mol. Cell Biol. 26, 8087–8098 (2006).
Acknowledgements
The authors apologize to colleagues whose work is not cited owing to space constraints. Research in S. J. Rhodes' laboratory is supported by NIH grant RO1 HD42024; K. L. Prince is supported by NIH grant F32 HD068113.
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E. C. Walvoord declares associations with the following companies: Eli Lilly (grant/research support), Novo Nordisk (speakers bureau). The other authors declare no competing interests.
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Prince, K., Walvoord, E. & Rhodes, S. The role of homeodomain transcription factors in heritable pituitary disease. Nat Rev Endocrinol 7, 727–737 (2011). https://doi.org/10.1038/nrendo.2011.119
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DOI: https://doi.org/10.1038/nrendo.2011.119
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