The hypothalamic peptide, gonadotropin-releasing hormone (GnRH), is the key neuroendocrine regulator of mammalian reproductive development and function. At the level of the anterior pituitary, GnRH binds to the GnRH receptor (GnRHR), located on the cell surface of pituitary gonadotropes, to stimulate the synthesis and release of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Levels of GnRHR in the gonadotrope are highly regulated, and the responses of gonadotropes to GnRH correlate directly with the concentration of GnRHR on the cell surface. Several hormones, most notably GnRH itself, are critical regulators of the GnRHR gene. GnRH is released in a pulsatile manner, with the frequency and amplitude of GnRH pulses varying temporally and developmentally. These patterns of pulsatile GnRH release lead to differential LH and FSH synthesis and secretion and are pivotal for the regulation of reproductive development and fertility. The mechanism by which the gonadotrope "decodes" GnRH pulse frequency to differentially control LH and FSH remains a major question in reproductive endocrinology. The long-term goal of this project is to identify the mechanisms underlying GnRH pulse frequency-dependent differential regulation of gonadotropin gene expression and thereby LH and FSH synthesis and secretion. The hypothesis to be tested is that cell surface levels of GnRHR, as determined by the pattern of pulsatile GnRH, are a critical component of the gonadotrope GnRH pulse frequency decoder, determining the signal transduction pathways and transcriptional networks activated by GnRH to ultimately dictate LH and FSH production. The specific objective of this proposal is to test this hypothesis by identifying the signal transduction pathways and transcriptional networks activated through the GnRHR at varying GnRH pulse frequencies in vitro and in vivo, and to determine the role of cell surface GnRHR in dictating these pathways. In the first aim, we will identify the signal transduction pathways activated by pulsatile GnRH to stimulate FSH? at low GnRHR levels, which correspond to low GnRH pulse frequencies. In the second aim, we will identify the signal transduction pathways activated by pulsatile GnRH to stimulate LH?, and to reduce FSH? stimulation, at high GnRHR levels, which correspond to high GnRH pulse frequencies. In the third aim, we will determine the effects of dysregulation of GnRHR expression by site-specific GnRHR gene modification on reproductive function in vivo in a genetic mouse model. Finally, in the fourth aim, we will determine the effects of gonadotrope-specific deletion of G?s or G?q/11 on reproductive function in vivo in genetic mouse models. The successful completion of these aims will lead to a better understanding of the nature of the GnRH pulse frequency decoder and will advance our knowledge about the role of the GnRHR in reproductive physiology. Identification of these regulatory pathways will provide insight relevant to the treatment of clinical conditions including polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea, disorders of pubertal maturation, and infertility.

Public Health Relevance

Regulation of gonadotropin expression by pulsatile GnRH through the GnRH receptor is essential for sexual development and reproduction in mammals. The objective of this proposal is to determine how the GnRH receptor signals at varying GnRH pulse frequencies and how the numbers of receptors influence these pathways. The identification of these pathways will provide insights relevant to the treatment of reproductive disorders, including polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea, disorders of pubertal maturation, and infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD019938-23
Application #
8735637
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Lamar, Charisee A
Project Start
1990-08-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
23
Fiscal Year
2014
Total Cost
$342,785
Indirect Cost
$141,095
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Martin, Cecilia; Navarro, VĂ­ctor M; Simavli, Serap et al. (2014) Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone. J Neurosci 34:6047-56
Ahow, Maryse; Min, Le; Pampillo, Macarena et al. (2014) KISS1R signals independently of G?q/11 and triggers LH secretion via the ?-arrestin pathway in the male mouse. Endocrinology 155:4433-46
Thompson, Iain R; Kaiser, Ursula B (2014) GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 385:28-35
Noel, Sekoni D; Abreu, Ana Paula; Xu, Shuyun et al. (2014) TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients. FASEB J 28:1924-37
Kaiser, Ursula B (2014) Editorial: advances in neuroscience: the BRAIN initiative and implications for neuroendocrinology. Mol Endocrinol 28:1589-91
Beneduzzi, Daiane; Trarbach, Ericka B; Min, Le et al. (2014) Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril 102:838-846.e2
Navarro, Victor M; Kaiser, Ursula B (2013) Metabolic influences on neuroendocrine regulation of reproduction. Curr Opin Endocrinol Diabetes Obes 20:335-41
Thompson, Iain R; Ciccone, Nick A; Xu, Shuyun et al. (2013) GnRH pulse frequency-dependent stimulation of FSH? transcription is mediated via activation of PKA and CREB. Mol Endocrinol 27:606-18
Ciccone, Nick A; Xu, Shuyun; Lacza, Charlemagne T et al. (2010) Frequency-dependent regulation of follicle-stimulating hormone beta by pulsatile gonadotropin-releasing hormone is mediated by functional antagonism of bZIP transcription factors. Mol Cell Biol 30:1028-40
Raivio, Taneli; Sidis, Yisrael; Plummer, Lacey et al. (2009) Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 94:4380-90

Showing the most recent 10 out of 61 publications