Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

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

doi:10.1074/jbc.m113.537696

Cited by 24 publications

(21 citation statements)

References 61 publications

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“…To our knowledge, however, there is no evidence that GnRH signals directly to the Fshb promoter via either of these proteins (39,43). This said, both newer and older data suggest that GnRH may stimulate FSH indirectly via regulation of TGF␤ superfamily ligands and/or their antagonists (135)(136)(137)(138)(139). Future efforts, particularly in vivo, should be committed to determining the extent to which GnRH regulation of FSH depends on activins or other members of the TGF␤ superfamily.…”

Section: What Are the Relative Roles Of Activins (Or Activinlike Ligamentioning

confidence: 80%

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Fortin

Ongaro

et al. 2015

Molecular Endocrinology

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The activins were discovered and named based on their abilities to stimulate FSH secretion and FSHβ (Fshb) subunit expression by pituitary gonadotrope cells. According to subsequent in vitro observations, activins also stimulate the transcription of the GnRH receptor (Gnrhr) and the activin antagonist, follistatin (Fst). Thus, not only do activins stimulate FSH directly, they have the potential to regulate both FSH and LH indirectly by modulating gonadotrope sensitivity to hypothalamic GnRH. Moreover, activins may negatively regulate their own actions by stimulating the production of one of their principal antagonists. Here, we describe our current understanding of the mechanisms through which activins regulate Fshb, Gnrhr, and Fst transcription in vitro. The activin signaling molecules SMAD3 and SMAD4 appear to partner with the winged-helix/forkhead transcription factor, forkhead box L2 (FOXL2), to regulate expression of all 3 genes. However, in vivo data paint a different picture. Although conditional deletion of Foxl2 and/or Smad4 in murine gonadotropes produces impairments in FSH synthesis and secretion as well as in pituitary Fst expression, Gnrhr mRNA levels are either unperturbed or increased in these animals. Surprisingly, gonadotrope-specific deletion of Smad3 alone or with Smad2 does not impair FSH production or fertility; however, mice harboring these mutations may express a DNA binding-deficient, but otherwise functional, SMAD3 protein. Collectively, the available data firmly establish roles for FOXL2 and SMAD4 in Fshb and Fst expression in gonadotrope cells, whereas SMAD3's role requires further investigation. Gnrhr expression, in contrast, appears to be FOXL2, SMAD4, and, perhaps, activin independent in vivo.

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Section: What Are the Relative Roles Of Activins (Or Activinlike Ligamentioning

confidence: 80%

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Fortin

Ongaro

et al. 2015

Molecular Endocrinology

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“…The human FSHB gene (MIM 136530;11p13; genomic sequence 4.2 kb), coding for the FSH β-subunit, consists of one non-coding exon plus two translated exons that encode the 129-amino acid preprotein. The mechanisms controlling the transcription of the FSHB gene are critical regulatory steps in the production of the FSH hormone [5][6][7][8]. These mechanisms are complex, involving the actions of tissue-specific and widely expressed transcription factors [9].…”

Section: Introductionmentioning

confidence: 99%

Impact of the FSHB gene -211G/T polymorphism on male gonadal function

Tamburino

Vignera

Tomaselli

et al. 2017

J Assist Reprod Genet

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“…We previously demonstrated that GnRH activation of G␣ s in L␤T2 cells promotes Lhb but suppresses Fshb gene expression via secretion of inhibin ␣ (1). Conversely, secreted GDF9 is an autocrine inducer of Fshb and is preferentially suppressed by high frequency GnRH pulses in L␤T2 cells (37).…”

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confidence: 98%

Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression

Choi¹,

Wang²,

Jia³

et al. 2016

Journal of Biological Chemistry

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Reproductive function is controlled by the pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH), which regulates the expression of the gonadotropins luteinizing hormone and FSH in pituitary gonadotropes. Paradoxically, Fshb gene expression is maximally induced at lower frequency GnRH pulses, which provide a very low average concentration of GnRH stimulation. We studied the role of secreted factors in modulating gonadotropin gene expression. Inhibition of secretion specifically disrupted gonadotropin subunit gene regulation but left early gene induction intact. We characterized the gonadotrope secretoproteome and global mRNA expression at baseline and after Gα knockdown, which has been found to increase Fshb gene expression (1). We identified 1077 secreted proteins or peptides, 19 of which showed mRNA regulation by GnRH or/and Gα knockdown. Among several novel secreted factors implicated in Fshb gene regulation, we focused on the neurosecretory protein VGF. Vgf mRNA, whose gene has been implicated in fertility (2), exhibited high induction by GnRH and depended on Gα In contrast with Fshb induction, Vgf induction occurred preferentially at high GnRH pulse frequency. We hypothesized that a VGF-derived peptide might regulate Fshb gene induction. siRNA knockdown or extracellular immunoneutralization of VGF augmented Fshb mRNA induction by GnRH. GnRH stimulated the secretion of the VGF-derived peptide NERP1. NERP1 caused a concentration-dependent decrease in Fshb gene induction. These findings implicate a VGF-derived peptide in selective regulation of the Fshb gene. Our results support the concept that signaling specificity from the cell membrane GnRH receptor to the nuclear Fshb gene involves integration of intracellular signaling and exosignaling regulatory motifs.

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Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

Cited by 24 publications

References 61 publications

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Minireview: Activin Signaling in Gonadotropes: What Does the FOX say… to the SMAD?

Impact of the FSHB gene -211G/T polymorphism on male gonadal function

Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression

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