Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone β-subunit (fshjβ) gene expression

Soon Gang Choi, Qian Wang, Jingjing Jia, Hanna Pincas, Judith L Turgeon, Stuart C. Sealfon

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses from the hypothalamus and regulates follicle-stimulating hormone/β-subunit (FSH/β) gene expression in pituitary gonadotropes in a frequency-sensitive manner. The mechanisms underlying its preferential and paradoxical induction of FSH/β by low frequency GnRH pulses are incompletely understood. Here, we identify growth differentiation factor 9 (GDF9) as a GnRH-suppressed autocrine inducer of FSH/β gene expression. GDF9 gene transcription and expression were preferentially decreased by high frequency GnRH pulses. GnRH regulation of GDF9 was concentration-dependent and involved ERK and PKA. GDF9 knockdown or immunoneutralization reduced FSH/β mRNA expression. Conversely, exogenous GDF9 induced FSH/β expression in immortalized gonadotropes and in mouse primary pituitary cells. GDF9 exposure increased FSH secretion in rat primary pituitary cells. GDF9 induced Smad2/3 phosphorylation, which was impeded by ALK5 knockdown and by activin receptor-like kinase (ALK) receptor inhibitor SB-505124, which also suppressed FSH/β expression. Smad2/3 knockdown indicated that FSH/β induction by GDF9 involved Smad2 and Smad3. FSH/β mRNA induction by GDF9 and GnRH was synergistic. We hypothesized that GDF9 contributes to a regulatory loop that tunes the GnRH frequencyresponse characteristics of the FSH/β gene. To test this, we determined the effects of GDF9 knockdown on FSH/β induction at different GnRH pulse frequencies using a parallel perifusion system. Reduction of GDF9 shifted the characteristic pattern of GnRH pulse frequency sensitivity. These results identify GDF9 as contributing to an incoherent feed-forward loop, comprising both intracellular and secreted components, that regulates FSH/β expression in response to activation of cell surface GnRH receptors.

Original languageEnglish (US)
Pages (from-to)16164-16175
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number23
DOIs
StatePublished - Jun 6 2014

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Growth Differentiation Factor 9
Follicle Stimulating Hormone
Gene expression
Gonadotropin-Releasing Hormone
Gene Expression
Genes
Activin Receptors
LHRH Receptors
Messenger RNA
Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone β-subunit (fshjβ) gene expression. / Choi, Soon Gang; Wang, Qian; Jia, Jingjing; Pincas, Hanna; Turgeon, Judith L; Sealfon, Stuart C.

In: Journal of Biological Chemistry, Vol. 289, No. 23, 06.06.2014, p. 16164-16175.

Research output: Contribution to journalArticle

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abstract = "Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses from the hypothalamus and regulates follicle-stimulating hormone/β-subunit (FSH/β) gene expression in pituitary gonadotropes in a frequency-sensitive manner. The mechanisms underlying its preferential and paradoxical induction of FSH/β by low frequency GnRH pulses are incompletely understood. Here, we identify growth differentiation factor 9 (GDF9) as a GnRH-suppressed autocrine inducer of FSH/β gene expression. GDF9 gene transcription and expression were preferentially decreased by high frequency GnRH pulses. GnRH regulation of GDF9 was concentration-dependent and involved ERK and PKA. GDF9 knockdown or immunoneutralization reduced FSH/β mRNA expression. Conversely, exogenous GDF9 induced FSH/β expression in immortalized gonadotropes and in mouse primary pituitary cells. GDF9 exposure increased FSH secretion in rat primary pituitary cells. GDF9 induced Smad2/3 phosphorylation, which was impeded by ALK5 knockdown and by activin receptor-like kinase (ALK) receptor inhibitor SB-505124, which also suppressed FSH/β expression. Smad2/3 knockdown indicated that FSH/β induction by GDF9 involved Smad2 and Smad3. FSH/β mRNA induction by GDF9 and GnRH was synergistic. We hypothesized that GDF9 contributes to a regulatory loop that tunes the GnRH frequencyresponse characteristics of the FSH/β gene. To test this, we determined the effects of GDF9 knockdown on FSH/β induction at different GnRH pulse frequencies using a parallel perifusion system. Reduction of GDF9 shifted the characteristic pattern of GnRH pulse frequency sensitivity. These results identify GDF9 as contributing to an incoherent feed-forward loop, comprising both intracellular and secreted components, that regulates FSH/β expression in response to activation of cell surface GnRH receptors.",
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AU - Sealfon, Stuart C.

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