The gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play an integral role in the reproductive axis. translating neural and hormonal input into precisely regulated output to achieve normal sexual development and regulation of gonadal function. The long-term objective of this project is to elucidate the molecular mechanisms underlying regulation of gonadotropin gene expression, information that will provide insight into both normal and abnormal reproductive function. In recent years, considerable progress has been made in the elucidation of the molecular mechanisms underlying tissue- specific and GnRH-stimulated expression of LHbeta gene. However, relatively little is known about the mechanisms of transcriptional regulation of the FSHbeta gene. The goal of this proposal is to explore mechanisms of tissue-specific and hormonally-regulated expression of the rat FSHbeta gene in vitro and in vivo, using the recently developed LbetaT2 cell line and transgenic mice as models. In the first aim, we will test our hypothesis that the homeodomain protein Pitx1 binds directly to specific elements in the FSHbeta promoter and interacts with other transcription factors to synergistically activate gonadotrope-specific and hormonally regulated FSHbeta gene transcription. Secondly, we will characterize the roles of the two interacting orphan nuclear receptors, SF-1 and DAX-1, in the regulation of FSHbeta gene expression, based on our hypothesis that SF-1 and DAX-1 have distinct effects on the FSHbeta and LHbeta genes, which may underlie some of the differential regulatory responses of FSH and LH that occur in vivo. In the third aim, we plan to identify and characterize cis-elements, and their cognate trans-factors, which mediate GnRH-regulated expression of the FSHbeta gene. Finally, we propose to characterize the mechanisms of transcriptional stimulation of the FSHbeta gene by activin, an important physiologic regulator of FSH production. By characterizing the factors that mediate tissue-specific and hormonally-regulated FSHbeta gene expression, we will be better able to elucidate the mechanisms underlying disorders of reproductive function, and may identify new targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD033001-06
Application #
6371046
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
De Paolo, Louis V
Project Start
1996-08-01
Project End
2006-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
6
Fiscal Year
2001
Total Cost
$289,832
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Thompson, Iain R; Ciccone, Nick A; Zhou, Qiongjie et al. (2016) GnRH Pulse Frequency Control of Fshb Gene Expression Is Mediated via ERK1/2 Regulation of ICER. Mol Endocrinol 30:348-60
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
Ciccone, Nick A; Kaiser, Ursula B (2009) The biology of gonadotroph regulation. Curr Opin Endocrinol Diabetes Obes 16:321-7
Jeong, Kyeong-Hoon; Gill, John C; Nosé, Vania et al. (2009) Expression of a gonadotropin-releasing hormone receptor-simian virus 40 T-antigen transgene has sex-specific effects on the reproductive axis. Endocrinology 150:3383-91
Ciccone, Nick A; Lacza, Charlemagne T; Hou, Melody Y et al. (2008) A composite element that binds basic helix loop helix and basic leucine zipper transcription factors is important for gonadotropin-releasing hormone regulation of the follicle-stimulating hormone beta gene. Mol Endocrinol 22:1908-23
Kaiser, Ursula B (2008) Genetic labeling: new approaches to creating a gonadotroph ""ID"". Endocrinology 149:2699-700
Kanasaki, Haruhiko; Bedecarrats, Gregoy Y; Kam, Kyung-Yoon et al. (2005) Gonadotropin-releasing hormone pulse frequency-dependent activation of extracellular signal-regulated kinase pathways in perifused LbetaT2 cells. Endocrinology 146:5503-13
Gregory, Susan J; Lacza, Charlemagne T; Detz, Alissa A et al. (2005) Synergy between activin A and gonadotropin-releasing hormone in transcriptional activation of the rat follicle-stimulating hormone-beta gene. Mol Endocrinol 19:237-54
Bedecarrats, Gregoy Y; O'Neill, Francis H; Norwitz, Errol R et al. (2003) Regulation of gonadotropin gene expression by Mullerian inhibiting substance. Proc Natl Acad Sci U S A 100:9348-53

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