Regulation of Gonadotropin-Releasing Hormone Gene Expression

Helen H. Kim

doi:10.1055/s-2007-984737

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2007; 25(5): 313-325
DOI: 10.1055/s-2007-984737

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

Abstract

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.

KEYWORDS

Gonadotropin-releasing hormone (GnRH) - transcription factors - gene regulation - tissue-specific expression - transgenic mice

Full Text

References

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