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 language | English (US) |
|---|---|
| Pages (from-to) | 16164-16175 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 289 |
| Issue number | 23 |
| DOIs | |
| State | Published - Jun 6 2014 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
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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 journal › Article
}
TY - JOUR
T1 - Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone β-subunit (fshjβ) gene expression
AU - Choi, Soon Gang
AU - Wang, Qian
AU - Jia, Jingjing
AU - Pincas, Hanna
AU - Turgeon, Judith L
AU - Sealfon, Stuart C.
PY - 2014/6/6
Y1 - 2014/6/6
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M113.537696
DO - 10.1074/jbc.M113.537696
M3 - Article
VL - 289
SP - 16164
EP - 16175
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 23
ER -