Outside the box signaling: Secreted factors modulate GnRH receptor-mediated gonadotropin regulation

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

doi:10.1016/j.mce.2013.08.015

Cited by 21 publications

(8 citation statements)

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“…Elucidating how cells decode specific extracellular stimuli, such as GnRH pulses, to direct gene expression patterns may require a broader view of cell signaling that encompasses a complex network involving both intracellular mediators and exosignaling circuits (Fig. 8) (81).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…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: 98%

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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“…Many studies have been conducted thus far to determine the mechanism by which GnRH differentially regulates the gonadotrophins LHb and FSHb. Pincas et al (65) have summarised these investigations in a recent comprehensive review (65).…”

Section: Gnrh Pulse Frequency-dependent Specific Regulation Of Gonadomentioning

confidence: 99%

Role of Pituitary Adenylate Cyclase‐Activating Polypeptide in Modulating Hypothalamus‐Pituitary Neuroendocrine Functions in Mouse Cell Models

Kanasaki

Oride

Kyo

2014

J Neuroendocrinology

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Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally identified as a hypothalamic activator of cyclic adenosine monophosphate production in pituitary cells. PACAP and its receptor are expressed not only in the central nervous system, but also in peripheral organs, and function to stimulate pituitary hormone synthesis and secretion as both a hypothalamicpituitary-releasing factor and an autocrine-paracrine factor within the pituitary. PACAP stimulates the expression of the gonadotrophin a, luteinising hormone (LH) b and follicle-stimulating hormone (FSH) b subunits, as well as the gonadotrophin-releasing hormone (GnRH) receptor and its own PACAP type I receptor (PAC1R) in gonadotrophin-secreting pituitary cells. In turn, GnRH, which is known to be a crucial component of gonadotrophin secretion, stimulates the expression of PACAP and PAC1R in gonadotrophs. In addition, PAC1R and PACAP modulate the functions of GnRH-producing neurones in the hypothalamus. This review summarises the current understanding of the possible roles of PACAP and PAC1R in modulating hypothalamus and pituitary neuroendocrine cells in the mouse models.

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Outside the box signaling: Secreted factors modulate GnRH receptor-mediated gonadotropin regulation

Cited by 21 publications

References 50 publications

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

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

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

Role of Pituitary Adenylate Cyclase‐Activating Polypeptide in Modulating Hypothalamus‐Pituitary Neuroendocrine Functions in Mouse Cell Models

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