Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency

Estee Stern, Frederique Ruf-Zamojski, Lisa Zalepa-King, Hanna Pincas, Soon Gang Choi, Charles S. Peskin, Fernand Hayot, Judith L. Turgeon, Stuart C. Sealfon

Research output: Contribution to journalArticle

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 subunits (FSH/LH). Contrary to Lhb, Fshb gene 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 of Fshb inhibitory factors (e.g. inhibin 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 for Fshb induction (e.g. growth differentiation factor 9). Simulations with all three models recapitulated the Fshb expression 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 of Fshb expression 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 induce Fshb, 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. Whereas Egr1 and Fos genes responded only to variations in average GNRH concentration, Fshb levels were sensitive to both average concentration and true pulse frequency. These results provide a foundation for understanding the role of multiple regulatory factors in modulating Fshb gene activity.

Original languageEnglish (US)
Pages (from-to)9815-9829
Number of pages15
JournalJournal of Biological Chemistry
Volume292
Issue number23
DOIs
StatePublished - Jun 9 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Stern, E., Ruf-Zamojski, F., Zalepa-King, L., Pincas, H., Choi, S. G., Peskin, C. S., Hayot, F., Turgeon, J. L., & Sealfon, S. C. (2017). Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency. Journal of Biological Chemistry, 292(23), 9815-9829. https://doi.org/10.1074/jbc.M117.783886