Semin Reprod Med 2007; 25(5): 313-325
DOI: 10.1055/s-2007-984737
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Regulation of Gonadotropin-Releasing Hormone Gene Expression

Helen H. Kim1
  • 1In Vitro Fertilization Program, Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
20. August 2007 (online)

ABSTRACT

Reproductive function is influenced by several internal and external cues, which ultimately exert their effects on the gonadotropin-releasing hormone (GnRH) neuron. As the final common pathway in the brain for regulating reproduction, GnRH neurons receive signals from multiple cell types, and alterations in GnRH production impact reproductive competence. Historically, the paucity of GnRH neurons and their scattered distribution in the brain have limited the study of GnRH gene expression. With transgenic technology, newer model systems (such as immortalized GnRH-expressing cell lines and GnRH-reporter gene transgenic mice) have been developed, making molecular studies possible. This article provides an update on the molecular mechanisms responsible for the regulation of GnRH gene expression, focusing on tissue-specific expression and transcriptional regulation. After an overview of GnRH gene structure, synthesis, and secretion, the model systems for studying GnRH neurons are examined. The molecular mechanisms that translate physiologic stimuli, such as nutritional status or stress, into changes in GnRH expression will be reviewed, concentrating on the regulatory regions within the GnRH gene promoter and the critical transcription factors.

REFERENCES

  • 1 Gore A C. GnRH: The Master Molecule of Reproduction. Norwell, MA; Kluwer Academic Publishers 2002
  • 2 Wray S. Development of gonadotropin-releasing hormone-1 neurons.  Front Neuroendocrinol. 2002;  23 292-316
  • 3 Gore A C. GnRH neurons: changes across the life cycle. In: Gore AC GnRH: The Master Molecule of Reproduction. Norwell, MA; Kluwer Academic 2002: 53-92
  • 4 Gore A C. Multiple GnRH molecules phylogeny and evolution. In: Gore AC GnRH: The Master Molecule of Reproduction. Norwell, MA; Kluwer Academic 2002
  • 5 Fernald R D, White R B. Gonadotropin-releasing hormone genes: phylogeny, structure, and functions.  Front Neuroendocrinol. 1999;  20 224-240
  • 6 Wetsel W C, Srinivasan S. Pro-GnRH processing.  Prog Brain Res. 2002;  141 221-241
  • 7 Gore A C, Roberts J L. Regulation of gonadotropin-releasing hormone gene expression in vivo and in vitro.  Front Neuroendocrinol. 1997;  18 209-245
  • 8 Gore A C. Gonadotropin-releasing hormone (GnRH) neurons: gene expression and neuroanatomical studies.  Prog Brain Res. 2002;  141 193-208
  • 9 Darnell Jr J E. Variety in the level of gene control in eukaryotic cells.  Nature. 1982;  297 365-371
  • 10 Zhen S, Dunn I C, Wray S et al.. An alternative gonadotropin-releasing hormone (GnRH) RNA splicing product found in cultured GnRH neurons and mouse hypothalamus.  J Biol Chem. 1997;  272 12620-12625
  • 11 Wierman M E. Gonadotropin-releasing hormone. In: Adashi EY, Rock JA, Rosenwaks Z Reproductive Endocrinology, Surgery, and Technology. Philadelphia; Lippincott-Raven 1996: 665-682
  • 12 Belsham D D, Lovejoy D A. Gonadotropin-releasing hormone: gene evolution, expression, and regulation.  Vitam Horm. 2005;  71 59-94
  • 13 Mellon P L, Windle J J, Goldsmith P C, Padula C A, Roberts J L, Weiner R I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis.  Neuron. 1990;  5 1-10
  • 14 Radovick S, Wray S, Lee E et al.. Migratory arrest of gonadotropin-releasing hormone neurons in transgenic mice.  Proc Natl Acad Sci USA. 1991;  88 3402-3406
  • 15 Fang Z, Xiong X, James A, Gordon D F, Wierman M E. Identification of novel factors that regulate GnRH gene expression and neuronal migration.  Endocrinology. 1998;  139 3654-3657
  • 16 Maggi R, Pimpinelli F, Molteni L, Milani M, Martini L, Piva F. Immortalized luteinizing hormone-releasing hormone neurons show a different migratory activity in vitro.  Endocrinology. 2000;  141 2105-2112
  • 17 Pimpinelli F, Redaelli E, Restano-Cassulini R et al.. Depolarization differentially affects the secretory and migratory properties of two cell lines of immortalized luteinizing hormone-releasing hormone (LHRH) neurons.  Eur J Neurosci. 2003;  18 1410-1418
  • 18 Wetsel W C, Valenca M M, Merchenthaler I et al.. Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons.  Proc Natl Acad Sci USA. 1992;  89 4149-4153
  • 19 Salvi R, Castillo E, Voirol M J et al.. Gonadotropin-releasing hormone-expressing neurons immortalized conditionally are activated by insulin: implication of the mitogen-activated protein kinase pathway.  Endocrinology. 2006;  147 816-826
  • 20 Jasoni C L, Todman M G, Strumia M M, Herbison A E. Cell type-specific expression of a genetically encoded calcium indicator reveals intrinsic calcium oscillations in adult gonadotropin-releasing hormone neurons.  J Neurosci. 2007;  27 860-867
  • 21 Spergel D J, Kruth U, Shimshek D R, Sprengel R, Seeburg P H. Using reporter genes to label selected neuronal populations in transgenic mice for gene promoter, anatomical, and physiological studies.  Prog Neurobiol. 2001;  63 673-686
  • 22 Herbison A E, Pape J R, Simonian S X, Skynner M J, Sim J A. Molecular and cellular properties of GnRH neurons revealed through transgenics in the mouse.  Mol Cell Endocrinol. 2001;  185 185-194
  • 23 Skynner M J, Slater R, Sim J A, Allen N D, Herbison A E. Promoter transgenics reveal multiple gonadotropin-releasing hormone-I-expressing cell populations of different embryological origin in mouse brain.  J Neurosci. 1999;  19 5955-5966
  • 24 Suter K J, Song W J, Sampson T L et al.. Genetic targeting of green fluorescent protein to gonadotropin-releasing hormone neurons: characterization of whole-cell electrophysiological properties and morphology.  Endocrinology. 2000;  141 412-419
  • 25 Spergel D J, Kruth U, Hanley D F, Sprengel R, Seeburg P H. GABA- and glutamate-activated channels in green fluorescent protein-tagged gonadotropin-releasing hormone neurons in transgenic mice.  J Neurosci. 1999;  19 2037-2050
  • 26 Suter K J, Wuarin J P, Smith B N, Dudek F E, Moenter S M. Whole-cell recordings from preoptic/hypothalamic slices reveal burst firing in gonadotropin-releasing hormone neurons identified with green fluorescent protein in transgenic mice.  Endocrinology. 2000;  141 3731-3736
  • 27 Sim J A, Skynner M J, Pape J R, Herbison A E. Late postnatal reorganization of GABA(A) receptor signalling in native GnRH neurons.  Eur J Neurosci. 2000;  12 3497-3504
  • 28 Kos C H. Cre/loxP system for generating tissue-specific knockout mouse models.  Nutr Rev. 2004;  62 243-246
  • 29 Morozov A, Kellendonk C, Simpson E, Tronche F. Using conditional mutagenesis to study the brain.  Biol Psychiatry. 2003;  54 1125-1133
  • 30 Shimshek D R, Kim J, Hubner M R et al.. Codon-improved Cre recombinase (iCre) expression in the mouse.  Genesis. 2002;  32 19-26
  • 31 Yoon H, Enquist L W, Dulac C. Olfactory inputs to hypothalamic neurons controlling reproduction and fertility.  Cell. 2005;  123 669-682
  • 32 Wintermantel T M, Campbell R E, Porteous R et al.. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility.  Neuron. 2006;  52 271-280
  • 33 Shimshek D R, Bus T, Grinevich V et al.. Impaired reproductive behavior by lack of GluR-B containing AMPA receptors but not of NMDA receptors in hypothalamic and septal neurons.  Mol Endocrinol. 2006;  20 219-231
  • 34 Clarke I J, Pompolo S. Synthesis and secretion of GnRH.  Anim Reprod Sci. 2005;  88 29-55
  • 35 Ebling F J. The neuroendocrine timing of puberty.  Reproduction. 2005;  129 675-683
  • 36 Knobil E. The neuroendocrine control of the menstrual cycle.  Recent Prog Horm Res. 1980;  36 53-88
  • 37 Yin W, Gore A C. Neuroendocrine control of reproductive aging: roles of GnRH neurons.  Reproduction. 2006;  131 403-414
  • 38 Wise P M, Krajnak K M, Kashon M L. Menopause: the aging of multiple pacemakers.  Science. 1996;  273 67-70
  • 39 Clarkson J, Herbison A E. Development of GABA and glutamate signaling at the GnRH neuron in relation to puberty.  Mol Cell Endocrinol. 2006;  254-255 32-38
  • 40 Ojeda S R, Lomniczi A, Mastronardi C et al.. Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach?.  Endocrinology. 2006;  147 1166-1174
  • 41 Kuohung W, Kaiser U B. GPR54 and KiSS-1: role in the regulation of puberty and reproduction.  Rev Endocr Metab Disord. 2006;  7(4) 257-263
  • 42 Dungan H M, Clifton D K, Steiner R A. Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion.  Endocrinology. 2006;  147 1154-1158
  • 43 Temple J L, Rissman E F. Nutrition, reproduction, and behavior.  Prog Brain Res. 2002;  141 303-314
  • 44 Gamba M, Pralong F P. Control of GnRH neuronal activity by metabolic factors: the role of leptin and insulin.  Mol Cell Endocrinol. 2006;  254-255 133-139
  • 45 Farooqi S, Rau H, Whitehead J, O'Rahilly S. ob gene mutations and human obesity.  Proc Nutr Soc. 1998;  57 471-475
  • 46 Kim H, Wolfe A, Cohen R N et al.. In vivo identification of a 107 bp promoter element mediating neuron-specific expression of mouse gonadotropin-releasing hormone.  Mol Endocrinol. 2007;  21 457-471
  • 47 Kim H H, DiVall S A, Deneau R M, Wolfe A. Insulin regulation of GnRH gene expression through MAP kinase signaling pathways.  Mol Cell Endocrinol. 2005;  242 42-49
  • 48 Chrousos G P, Torpy D J, Gold P W. Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications.  Ann Intern Med. 1998;  129 229-240
  • 49 Ferin M. Clinical review 105: stress and the reproductive cycle.  J Clin Endocrinol Metab. 1999;  84 1768-1774
  • 50 Tellam D J, Perone M J, Dunn I C et al.. Direct regulation of GnRH transcription by CRF-like peptides in an immortalized neuronal cell line.  Neuroreport. 1998;  9 3135-3140
  • 51 Ahima R S, Harlan R E. Glucocorticoid receptors in LHRH neurons.  Neuroendocrinology. 1992;  56 845-850
  • 52 Chandran U R, Attardi B, Friedman R, Dong K W, Roberts J L, DeFranco D B. Glucocorticoid receptor-mediated repression of gonadotropin-releasing hormone promoter activity in GT1 hypothalamic cell lines.  Endocrinology. 1994;  134 1467-1474
  • 53 Chandran U R, Attardi B, Friedman R, Zheng Z, Roberts J L, DeFranco D B. Glucocorticoid repression of the mouse gonadotropin-releasing hormone gene is mediated by promoter elements that are recognized by heteromeric complexes containing glucocorticoid receptor.  J Biol Chem. 1996;  271 20412-20420
  • 54 Chandran U R, Warren B S, Baumann C T, Hager G L, DeFranco D B. The glucocorticoid receptor is tethered to DNA-bound Oct-1 at the mouse gonadotropin-releasing hormone distal negative glucocorticoid response element.  J Biol Chem. 1999;  274 2372-2378
  • 55 Herbison A E, Pape J R. New evidence for estrogen receptors in gonadotropin-releasing hormone neurons.  Front Neuroendocrinol. 2001;  22 292-308
  • 56 Petersen S L, Ottem E N, Carpenter C D. Direct and indirect regulation of gonadotropin-releasing hormone neurons by estradiol.  Biol Reprod. 2003;  69 1771-1778
  • 57 Radovick S, Wray S, Muglia L et al.. Steroid hormone regulation and tissue-specific expression of the human GnRH gene in cell culture and transgenic animals.  Horm Behav. 1994;  28 520-529
  • 58 Poletti A, Melcangi R C, Negri-Cesi P, Maggi R, Martini L. Steroid binding and metabolism in the luteinizing hormone-releasing hormone-producing neuronal cell line GT1-1.  Endocrinology. 1994;  135 2623-2628
  • 59 Roy D, Angelini N L, Belsham D D. Estrogen directly represses gonadotropin-releasing hormone (GnRH) gene expression in estrogen receptor-alpha (ERalpha)- and ERbeta-expressing GT1-7 GnRH neurons.  Endocrinology. 1999;  140 5045-5053
  • 60 Givens M L, Kurotani R, Rave-Harel N, Miller N L, Mellon P L. Phylogenetic footprinting reveals evolutionarily conserved regions of the gonadotropin-releasing hormone gene that enhance cell-specific expression.  Mol Endocrinol. 2004;  18 2950-2966
  • 61 Chandran U R, DeFranco D B. Regulation of gonadotropin-releasing hormone gene transcription.  Behav Brain Res. 1999;  105 29-36
  • 62 Eraly S A, Mellon P L. Regulation of gonadotropin-releasing hormone transcription by protein kinase C is mediated by evolutionarily conserved promoter-proximal elements.  Mol Endocrinol. 1995;  9 848-859
  • 63 Whyte D B, Lawson M A, Belsham D D et al.. A neuron-specific enhancer targets expression of the gonadotropin-releasing hormone gene to hypothalamic neurosecretory neurons.  Mol Endocrinol. 1995;  9 467-477
  • 64 Nelson S B, Lawson M A, Kelley C G, Mellon P L. Neuron-specific expression of the rat gonadotropin-releasing hormone gene is conferred by interactions of a defined promoter element with the enhancer in GT1-7 cells.  Mol Endocrinol. 2000;  14 1509-1522
  • 65 Lawson M A, Macconell L A, Kim J, Powl B T, Nelson S B, Mellon P L. Neuron-specific expression in vivo by defined transcription regulatory elements of the GnRH gene.  Endocrinology. 2002;  143 1404-1412
  • 66 Kim H H, Wolfe A, Cohen R N et al.. In vivo identification of a 107-base pair promoter element mediating neuron-specific expression of mouse gonadotropin-releasing hormone.  Mol Endocrinol. 2007;  21 457-471
  • 67 Thanky N R, Slater R, Herbison A E. Sex differences in estrogen-dependent transcription of gonadotropin-releasing hormone (GnRH) gene revealed in GnRH transgenic mice.  Endocrinology. 2003;  144 3351-3358
  • 68 Pape J R, Skynner M J, Allen N D, Herbison A E. Transgenics identify distal 5′- and 3′-sequences specifying gonadotropin-releasing hormone expression in adult mice.  Mol Endocrinol. 1999;  13 2203-2211
  • 69 Kim H H, Wolfe A, Smith G R, Tobet S A, Radovick S. Promoter sequences targeting tissue-specific gene expression of hypothalamic and ovarian gonadotropin-releasing hormone in vivo.  J Biol Chem. 2002;  277 5194-5202
  • 70 Wolfe A, Kim H H, Tobet S, Stafford D E, Radovick S. Identification of a discrete promoter region of the human GnRH gene that is sufficient for directing neuron-specific expression: a role for POU homeodomain transcription factors.  Mol Endocrinol. 2002;  16 435-449
  • 71 Kelley C G, Lavorgna G, Clark M E, Boncinelli E, Mellon P L. The Otx2 homeoprotein regulates expression from the gonadotropin-releasing hormone proximal promoter.  Mol Endocrinol. 2000;  14 1246-1256
  • 72 Mallamaci A, Di Blas E, Briata P, Boncinelli E, Corte G. OTX2 homeoprotein in the developing central nervous system and migratory cells of the olfactory area.  Mech Dev. 1996;  58 165-178
  • 73 Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode.  Proc Natl Acad Sci USA. 1989;  86 8132-8136
  • 74 Nelson S B, Eraly S A, Mellon P L. The GnRH promoter: target of transcription factors, hormones, and signaling pathways.  Mol Cell Endocrinol. 1998;  140 151-155
  • 75 Wierman M E, Xiong X, Kepa J K et al.. Repression of gonadotropin-releasing hormone promoter activity by the POU homeodomain transcription factor SCIP/Oct-6/Tst-1: a regulatory mechanism of phenotype expression?.  Mol Cell Biol. 1997;  17 1652-1665
  • 76 Clark M E, Mellon P L. The POU homeodomain transcription factor Oct-1 is essential for activity of the gonadotropin-releasing hormone neuron-specific enhancer.  Mol Cell Biol. 1995;  15 6169-6177
  • 77 Vazquez-Martinez R, Leclerc G M, Wierman M E, Boockfor F R. Episodic activation of the rat GnRH promoter: role of the homeoprotein oct-1.  Mol Endocrinol. 2002;  16 2093-2100
  • 78 Andersen B, Rosenfeld M G. POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease.  Endocr Rev. 2001;  22 2-35
  • 79 Tang Q, Mazur M, Mellon P L. The protein kinase C pathway acts through multiple transcription factors to repress gonadotropin-releasing hormone gene expression in hypothalamic GT1-7 neuronal cells.  Mol Endocrinol. 2005;  19 2769-2779
  • 80 Belsham D D, Mellon P L. Transcription factors Oct-1 and C/EBPbeta (CCAAT/enhancer-binding protein-beta) are involved in the glutamate/nitric oxide/cyclic-guanosine 5′-monophosphate-mediated repression of mediated repression of gonadotropin-releasing hormone gene expression.  Mol Endocrinol. 2000;  14 212-228
  • 81 Rave-Harel N, Givens M L, Nelson S B et al.. TALE homeodomain proteins regulate gonadotropin-releasing hormone gene expression independently and via interactions with Oct-1.  J Biol Chem. 2004;  279 30287-30297
  • 82 Rave-Harel N, Miller N L, Givens M L, Mellon P L. The Groucho-related gene family regulates the gonadotropin-releasing hormone gene through interaction with the homeodomain proteins MSX1 and OCT1.  J Biol Chem. 2005;  280 30975-30983
  • 83 Givens M L, Rave-Harel N, Goonewardena V D et al.. Developmental regulation of gonadotropin-releasing hormone gene expression by the MSX and DLX homeodomain protein families.  J Biol Chem. 2005;  280 19156-19165
  • 84 Lawson M A, Whyte D B, Mellon P L. GATA factors are essential for activity of the neuron-specific enhancer of the gonadotropin-releasing hormone gene.  Mol Cell Biol. 1996;  16 3596-3605
  • 85 Lawson M A, Buhain A R, Jovenal J C, Mellon P L. Multiple factors interacting at the GATA sites of the gonadotropin-releasing hormone neuron-specific enhancer regulate gene expression.  Mol Endocrinol. 1998;  12 364-377
  • 86 Lawson M A, Mellon P L. Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse.  Mol Cell Endocrinol. 1998;  140 157-161

Helen H KimM.D. 

Director, In Vitro Fertilization Program, Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology

The University of Chicago, 5841 South Maryland, MC 2050, Chicago, IL 60637

eMail: hkim@babies.bsd.uchicago.edu