title: Modeling and high-throughput experimental data uncover the mechanisms underlyingFshbgene sensitivity to gonadotropin-releasing hormone pulse frequency.
abstract: Neuroendocrine control of reproduction by brain-secreted pulses of gonadotropin-releasing hormone (GnRH) represents a longstanding puzzle about extracellular signal decoding mechanisms. GnRH regulates the pituitary gonadotropin's follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are heterodimers specified by unique β subunits (FSHβ/LHβ). Contrary toLhb,Fshbgene induction has a preference for low-frequency GnRH pulses. To clarify the underlying regulatory mechanisms, we developed three biologically anchored mathematical models: 1) parallel activation ofFshbinhibitory factors (e.g.inhibin α and VGF nerve growth factor-inducible), 2) activation of a signaling component with a refractory period (e.g.G protein), and 3) inactivation of a factor needed forFshbinduction (e.g.growth differentiation factor 9). Simulations with all three models recapitulated theFshbexpression levels obtained in pituitary gonadotrope cells perifused with varying GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration, and pulse frequency revealed that the apparent frequency-dependent pattern ofFshbexpression in model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed "true" pulse frequency sensing. To resolve which components of this GnRH signal induceFshb, we developed a high-throughput parallel experimental system. We analyzed over 4,000 samples in experiments with varying near-physiological GnRH concentrations and pulse patterns. WhereasEgr1andFosgenes responded only to variations in average GnRH concentration,Fshblevels were sensitive to both average concentration and true pulse frequency. These results provide a foundation for understanding the role of multiple regulatory factors in modulatingFshbgene activity.
authors.affiliation: From the Department of Neurology and.
authors.forename: Estee
authors.initials: E
authors.lastname: Stern
authors.affiliation: From the Department of Neurology and.
authors.forename: Frederique
authors.initials: F
authors.lastname: Ruf-Zamojski
authors.affiliation: From the Department of Neurology and.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zalepa-King
authors.affiliation: From the Department of Neurology and.
authors.forename: Hanna
authors.initials: H
authors.lastname: Pincas
authors.affiliation: From the Department of Neurology and.
authors.forename: Soon Gang
authors.initials: SG
authors.lastname: Choi
authors.affiliation: the Courant Institute of Mathematical Sciences and Center for Neural Science, New York University, New York, New York 10012, and.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Peskin
authors.affiliation: From the Department of Neurology and.
authors.forename: Fernand
authors.initials: F
authors.lastname: Hayot
authors.affiliation: the Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of California, Davis, California 95616.
authors.forename: Judith L
authors.initials: JL
authors.lastname: Turgeon
authors.affiliation: From the Department of Neurology and stuart.sealfon@mssm.edu.|the Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Stuart C
authors.identifier: 0000-0001-5791-1217
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D003198:Computer Simulation; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis*; D006801:Humans; D037101:Luteinizing Hormone, beta Subunit / Q000096:biosynthesis; D008954:Models, Biological; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D037201:Follicle Stimulating Hormone, beta Subunit; D037101:Luteinizing Hormone, beta Subunit; D016760:Proto-Oncogene Proteins c-fos; D007987:Gonadotropin-Releasing Hormone
keywords: G protein; GnRH pulse frequency; average GnRH concentration; follicle-stimulating hormone (FSH); gene expression; gene regulation; gonadotrope; mathematical modeling