Regulation of gonadotrope signaling and gonadotropin gene expression are central to the pathophysiology and treatment of a wide spectrum of diseases, including infertility, polycystic ovarian syndrome and gonadal hormone-dependent tumors. The major regulator of the gonadotropin genes LH and FSH is GnRH, which is released in short pulses the frequency of which varies during the female reproductive cycle. LH and FSH are differentially induced by GnRH, depending on the pulse frequency. Based on our recent discovery of several new secreted peptides that differentially regulate gonadotropin genes and on results of mathematical modeling, we hypothesize that control of gonadotropin gene expression and its frequency decoding is an emergent property of a distributed regulatory network including both intracellular signaling pathways and extracellular autocrine/paracrine factors. We plan to pursue a comprehensive study of the gonadotrope secretopeptidome and its regulation to identify new gonadotropin gene regulatory mechanisms and to develop a mathematical model to provide a comprehensive, testable and predictive framework for integrating the research in this field. We propose the following Specific Aims: 1. Characterize the gonadotrope secretopeptidome and study its regulation. iTRAQ secretopeptidome measurements from gonadotrope cell lines obtained under conditions that differentially regulate LH? and FSH? expression will be correlated with transcriptome assays using RNA-seq. Gonadotropin gene regulators will be selected by statistics and by a new computational approach we propose to develop that will infer subnetwork regulation from simultaneous analysis of these new gene expression and peptidomic datasets in the context of Bayesian integration of public datasets. 2. Study key secreted peptides and their mechanisms in gonadotrope regulation. Our initial secretopeptidome and RNAi experiments have identified several novel autocrine gonadotropin regulatory factors. The role of each factor in frequency- dependent regulation of gonadotropin secretion will be explored. Additional secreted gonadotropin gene regulatory candidates identified in Aim I will also be studied. 3. Develop and experimentally validate a model for gonadotropin gene frequency control. Several mechanisms for gonadotropin frequency decoding have been proposed and new regulatory loops are emerging from our work and that of other researchers. These mechanisms will be evaluated through a cycle of formal mathematical modeling, prediction, biological experiment and model refinement. Overall, this research program has the potential to identify and to characterize the mechanisms of action of new extracellular regulators of gonadotropin gene expression and to establish a model for GnRH frequency decoding and gonadotropin gene regulation.

Public Health Relevance

The gonadotrope cell is located at the base of the brain in the pituitary gland. Its control is important for normal reproductive health and for treating infertility and several diseases such as polycystic ovarian syndrome and certain common hormone-responsive cancers. We will use new research techniques to find new factors that affect these cells and to learn how they work together to influence its function in health and disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Blondel, Olivier
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Ruf-Zamojski, Frederique; Fribourg, Miguel; Ge, Yongchao et al. (2018) Regulatory Architecture of the L?T2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone. Front Endocrinol (Lausanne) 9:34
Fribourg, Miguel; Logothetis, Diomedes E; González-Maeso, Javier et al. (2017) Elucidation of molecular kinetic schemes from macroscopic traces using system identification. PLoS Comput Biol 13:e1005376
Stern, Estee; Ruf-Zamojski, Frederique; Zalepa-King, Lisa et al. (2017) Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency. J Biol Chem 292:9815-9829
Choi, Soon Gang; Wang, Qian; Jia, Jingjing et al. (2016) Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression. J Biol Chem 291:21322-21334
Choi, Soon Gang; Wang, Qian; Jia, Jingjing et al. (2014) Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone ?-subunit (FSH?) gene expression. J Biol Chem 289:16164-75
Wang, Qian; Chikina, Maria D; Pincas, Hanna et al. (2014) Homer1 alternative splicing is regulated by gonadotropin-releasing hormone and modulates gonadotropin gene expression. Mol Cell Biol 34:1747-56
Pincas, Hanna; Choi, Soon Gang; Wang, Qian et al. (2014) Outside the box signaling: secreted factors modulate GnRH receptor-mediated gonadotropin regulation. Mol Cell Endocrinol 385:56-61
Wang, Qian; Chikina, Maria; Zaslavsky, Elena et al. (2013) ?-catenin regulates GnRH-induced FSH? gene expression. Mol Endocrinol 27:224-37
Choi, Soon-Gang; Jia, Jingjing; Pfeffer, Robert L et al. (2012) G proteins and autocrine signaling differentially regulate gonadotropin subunit expression in pituitary gonadotrope. J Biol Chem 287:21550-60
Yuen, Tony; Choi, Soon Gang; Pincas, Hanna et al. (2012) Optimized amplification and single-cell analysis identify GnRH-mediated activation of Rap1b in primary rat gonadotropes. Mol Cell Endocrinol 350:10-9

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