The Bone Morphogenetic Protein 15 Up-Regulates the Anti-Müllerian Hormone Receptor Expression in Granulosa Cells

Aimar, Pierre; Estienne, Anthony; Racine, Chrystèle; Picard, Jean‐Yves; Fanchin, Rénato; Crespo, Belén Lahoz; Alabart, J. L.; Folch, J.; Jarrier, Peggy; Fabre, Stéphane; Monniaux, Danielle; Clemente, Nathalie di

doi:10.1210/jc.2015-4066

Cited by 46 publications

(36 citation statements)

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“…It has been previously demonstrated that GDF9 slightly enhances the stimulatory effect of BMP15 alone on AMH expression in ovine GCs obtained from preantral follicles (Pierre et al 2016). In contrast, we observed a strong synergism between GDF9 and BMP15 on the expression of AMH in humans, whereas either factor has negligible effects on AMH.…”

Section: Discussionmentioning

confidence: 98%

“…However, it is also possible that the receptors used by the heterodimers are not expressed in ovine GCs or that the heterodimers are more active in human than in ovine GCs. An example of this possibility is that in ovine GCs, Pierre et al (Pierre et al 2016) could show an increase in AMH promoter activity after treatment with GDF9 and BMP15. In contrast, we were not able to do so, suggesting species-specific differences.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

et al. 2017

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The regulation of AMH production by follicular cells is poorly understood. The purpose of this study was to determine the role of the oocyte-secreted factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), on AMH production in primary human cumulus cells. Cumulus cells from IVF patients were cultured with a combination of GDF9, BMP15, recombinant FSH, and specific signaling inhibitors. Stimulation with GDF9 or BMP15 separately had no significant effect on AMH mRNA levels. In contrast, simultaneous stimulation with GDF9 and BMP15 (G+B) resulted in a significant increase in AMH mRNA expression. Increasing concentration of G+B (0.6, 2.5, 5 and 10 ng/ml) stimulated AMH in a dose-dependent manner, showing a maximal effect at 5 ng/ml. Western blot analyses revealed an average 16-fold increase in AMH protein levels in cells treated with G+B when compared to controls. FSH co-treatment decreased the stimulation of AMH expression by G+B. The stimulatory effect of G+B on the expression of AMH was significantly decreased by inhibitors of the SMAD2/3 signaling pathway. These findings show for the first time that AMH production is regulated by oocyte-secreted factors in primary human cumulus cells. Moreover, our novel findings establish that the combination of GDF9 + BMP15 potently stimulates AMH expression.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

et al. 2017

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“…Studies on the pathogenesis of ovarian cysts must consider many potential contributing factors (Fitko et al, 1995(Fitko et al, , 1996Kozłowska et al, 2013;Pierre et al, 2016). As such, it is not yet possible to exclude contributions by BMP-15 and GDF-9 during cyst formation Błaszczyk, 2014, 2016).…”

Section: Discussionmentioning

confidence: 99%

The relationships between transforming growth factors <i>β</i> and free thyroxine and progesterone in the ovarian cysts, preovulatory follicles, and the serum of sows

Stankiewicz

2017

Arch. Anim. Breed.

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Abstract. The aim of the study was to determine the relationships between bone morphogenetic protein 15 (BMP-15) and growth differentiation factor 9 (GDF-9) concentrations and free thyroxine (FT 4 ) and progesterone (P 4 ) concentrations in follicular cysts, preovulatory follicles, and the serum of sows (cyst-bearing (n = 26) and non-cyst-bearing (n = 26)). FT 4 and P 4 concentrations were higher in the cystic fluid than in the fluid of preovulatory follicles (p < 0.01 and p < 0.05 respectively). BMP-15 and GDF-9 concentrations were higher in the serum of cyst-bearing sows than non-cyst-bearing sows (p < 0.05) and higher in the cystic fluid than in the follicular fluid (p < 0.05). In the cysts and preovulatory follicles, GDF-9 concentration was higher than in serum (p < 0.01). FT 4 concentration in the serum of cystic sows was correlated with BMP-15 (r = 0.50, p < 0.05) and GDF-9 (r = 0.62, p < 0.01) concentrations in serum. In the serum of non-cyst-bearing sows, a positive correlation between P 4 concentration and BMP-15 concentration (r = 0.60, p < 0.01) was detected.These data will help provide insight into the role of BMP-15, GDF-9, FT 4 , and P 4 during cyst formation in sows.

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“…A 2,252 (–2,199/+53)-bp human AMHR2 promoter (Ref-SeqGene NG-015981) [31, 40] was prepared by cloning successively a 428 (–375/+53)-bp fragment and a 1,825-bp distal promoter fragment (–2,199/–374) into the Bgl II and Hin dIII sites of the pGL2-basic vector. The short construct contains only the 428-bp fragment (428-h AMHR2 -Luc).…”

Section: Methodsmentioning

confidence: 99%

“…FSH and estradiol were reported to downregulate Amhr2 transcripts in rat ovarian follicles [37], and an inhibitory effect of LH and estradiol on AMHR2 mRNA levels was reported in human luteinized granulosa cells [38, 39]. Contrasting with gonadotropins, bone morphogenetic protein 4 (BMP4) and BMP15 were recently demonstrated to upregulate AMHR2 mRNA levels in human granulosa cells through transcriptional activation of the AMHR2 promoter [40]. However, the signaling pathways and mechanisms by which these hormones regulate the transcriptional activity of the AMHR2 gene are still unknown.…”

Section: Introductionmentioning

confidence: 99%

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

et al. 2018

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Background/Objectives: Anti-Müllerian hormone (AMH) signaling is critical for sexual differentiation and gonadal function. AMH receptor type 2 (AMHR2) is expressed in extragonadal sites such as brain, and pituitary and emerging evidence indicates that AMH biological action is much broader than initially thought. We recently reported that AMH signaling enhances follicle-stimulating hormone synthesis in pituitary gonadotrope cells. However, mechanisms regulating AMHR2 expression in these extragonadal sites remain to be explored. Method/Results: Here, we demonstrated in perifused murine LβT2 gonadotrope cells that Amhr2 expression is differentially regulated by GnRH pulse frequency with an induction under high GnRH pulsatility. Furthermore, we showed that GnRH transactivates the human AMHR2 promoter in LβT2 cells. Successive deletions of the promoter revealed the importance of a short proximal region (–53/–37 bp) containing an Egr1 binding site. Using site-directed mutagenesis of Egr1 motif and siRNA mediated-knockdown of Egr1, we demonstrated that Egr1 mediates basal and GnRH-dependent activity of the promoter, identifying Egr1 as a new transcription factor controlling hAMHR2 expression. We also showed that SF1 and β-catenin are required for basal promoter activity and demonstrated that both factors contribute to the GnRH stimulatory effect, independently of their respective binding sites. Furthermore, using a constitutively active mutant of FOXO1, we identified FOXO1 as a negative regulator of basal and GnRH-dependent AMHR2 expression in gonadotrope cells. Conclusions: This study identifies GnRH as a regulator of human AMHR2 expression, further highlighting the importance of AMH signaling in the regulation of gonadotrope function.

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The Bone Morphogenetic Protein 15 Up-Regulates the Anti-Müllerian Hormone Receptor Expression in Granulosa Cells

Abstract: Altogether, these results suggest that the mechanisms of action of BMP15 on AMHR2 and AMH expression are different, and that by stimulating AMHR2 and AMH expression in GCs BMP15 enhances AMH inhibitory actions in GCs.

Cited by 46 publications

References 41 publications

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

The relationships between transforming growth factors <i>β</i> and free thyroxine and progesterone in the ovarian cysts, preovulatory follicles, and the serum of sows

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

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The Bone Morphogenetic Protein 15 Up-Regulates the Anti-Müllerian Hormone Receptor Expression in Granulosa Cells

Abstract: Altogether, these results suggest that the mechanisms of action of BMP15 on AMHR2 and AMH expression are different, and that by stimulating AMHR2 and AMH expression in GCs BMP15 enhances AMH inhibitory actions in GCs.

Cited by 46 publications

References 41 publications

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

Regulation of AMH by oocyte-specific growth factors in human primary cumulus cells

The relationships between transforming growth factors &lt;i&gt;β&lt;/i&gt; and free thyroxine and progesterone in the ovarian cysts, preovulatory follicles, and the serum of sows

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

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The relationships between transforming growth factors <i>β</i> and free thyroxine and progesterone in the ovarian cysts, preovulatory follicles, and the serum of sows