Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

Lee, Katharine B; Khivansara, Vishal; Santos, Michelle M; Lamba, Pankaj; Yuen, Tony; Sealfon, Stuart C.; Bernard, Daniel J.

doi:10.1677/jme.1.02196

Cited by 52 publications

(56 citation statements)

References 71 publications

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“…These proteins can affect embryonic development and the formation of bones and organs, playing a critical role in the early mammalian development and nervous system differentiation. Recent data showed that bone morphogenetic proteins stimulate FSHβ transcription (Lee et al, 2007;Ho and Bernard, 2009). PTGFRN can inhibit prostaglandin F2α by interacting with its receptor.…”

Section: Discussionmentioning

confidence: 99%

Identification of target genes for adenohypophysis-prefer miR-7 and miR-375 in cattle

et al. 2015

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ABSTRACT. In this study, expression levels of miRNAs (miRNAs), miR-375 and miR-7, were detected in different tissues of cattle to determine whether adenohypophysis-prefer or exclusively expressed miRNAs, and target genes could be predicted by TargetScan, RNA22, and other software. Target genes related to pituitary function or reproductive traits were identified using a dual-luciferase assay. miR-375 and miR-7 were expressed differently in various tissues. miR-375 and miR-7 showed higher expression in the adenohypophysis, and there was a significant difference compared with expression in other tissues (P < 0.01). The binding sites for miR-7 were the mRNAs of bone morphogenetic protein receptor type II (BMPR2), prostaglandin F2 receptor negative regulator, gonadotropin-releasing hormone receptor, follicle-stimulating hormoneβ, somatostatin receptor 1, and interleukin-1β by bioinformatic analysis; similarly, the mRNAs of BMPR2 and leptin contained binding sites for miR-375, suggesting that these genes are affected by miR-7 or miR-375. Dual-luciferase reporter assays showed that miR-7 regulated (2015) prostaglandin F2 receptor negative regulator expression, while miR-375 regulated BMPR2 expression. The mutated plasmid and miRNA mimics were used to co-transfect NIH3T3 cells; luciferase reporter assays showed that the inhibition of luciferase activity in the wild-type cells dramatically decreased from 75 to 26% with a 3-5-nucleotide mismatch mutation into the seed region of miR-7. miR-375 had nearly lost the ability to inhibit luciferase activity, suggesting that GTCTTCC is the site of interaction between miR-7 and the prostaglandin F2 receptor negative regulator sequence and that GAACAAA is the site of interaction between miR-375 and the BMPR2 sequence.

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Section: Discussionmentioning

confidence: 99%

Identification of target genes for adenohypophysis-prefer miR-7 and miR-375 in cattle

et al. 2015

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“…We therefore examined the potential for GDF9 to display either 1) autocrine actions on FSH synthesis and secretion by gonadotrophs in the manner of activin that is subject to antagonism by inhibin (Corrigan et al 1991, Li et al 1998 or 2) synergism with activin to stimulate FSH production in the manner of BMP (Lee et al 2007b, Nicol et al 2008. However, GDF9 (1-50 ng/ml) did not significantly increase FSH secretion (Fig.…”

Section: Lack Of Gdf9 Effects On Fsh Secretion By Rat and Mouse Gonadmentioning

confidence: 99%

Extra-ovarian expression and activity of growth differentiation factor 9

Wang¹,

Nicholls²,

Stanton³

et al. 2009

Journal of Endocrinology

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Growth differentiation factor 9 (GDF9) produced within the ovary plays an essential role during follicle maturation through actions on granulosa cells, but extra-ovarian expression, signalling and actions of GDF9 are less well characterised. The present studies confirm GDF9 expression in the mouse testis, pituitary gland and adrenocortical cancer (AC) cells, and establish its expression in LbT2 gonadotrophs, and in mouse adrenal glands, particularly foetal and neonatal cortical cells. AC, LbT2, TM3 Leydig and TM4 Sertoli cells express the requisite GDF9 binding signalling components, particularly activin receptor-like kinase (ALK) 5 and the bone morphogenetic protein (BMP)/GDF type II receptor, BMPRII (BMPR2). We therefore compared GDF9 activation of these potential extra-ovarian target cell types with its activation of granulosa cells. Recombinant mouse GDF9 stimulated expression of activin/transforming growth factorb-responsive reporters, pGRAS-luc or pAR3-lux, in TM4 and AC cells (IC50Z145 ng/ml in the latter case), and two granulosa cell lines, KGN and COV434. The ALK4/5/7 inhibitor, SB431542, blocked GDF9 activity in each case. By contrast, GDF9 lacked specific effects on TM3 cells and rat primary pituitary and mouse LbT2 gonadotrophs. Our findings show that GDF9 regulates the expression of R-SMAD2/3-responsive reporter genes through ALK4, 5 or 7 in extra-ovarian (adrenocortical and Sertoli) cells with similar potency and signalling pathway to its actions on granulosa cells, but suggest that expression of BMPRII, ALK5 (TGFBR1) and R-SMADs 2 and 3 may not be sufficient for a cell to respond to GDF9.

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“…The effect on basal activity suggested that endogenous signaling via one or more of these receptors might contribute to the high 'basal'Hsd17b1 expression and 17b-HSD1 enzymatic activity in these cells. We previously showed that the Inhbb, but not Inhba subunit is expressed in LbT2 cells (Lee et al 2007). Homodimers of the INHBB protein form activin B. Activin B was implicated as the physiologically relevant activin in gonadotropes in vivo (Roberts et al 1989, Corrigan et al 1991, DePaolo et al 1992.…”

Section: Resultsmentioning

confidence: 99%

Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

Bąk¹,

Carpio²,

Kipp³

et al. 2009

Journal of Endocrinology

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Activins are pleiotropic members of the TGFb superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17b-hydroxysteroid dehydrogenase type I (17b-HSD1; Hsd17b1), as an activinresponsive gene in immortalized gonadotrope cells, LbT2. 17b-HSD1 catalyzes the conversion of estrone to the more active 17b-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediateearly fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17b-estradiol synthesis.

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Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

Cited by 52 publications

References 71 publications

Identification of target genes for adenohypophysis-prefer miR-7 and miR-375 in cattle

Identification of target genes for adenohypophysis-prefer miR-7 and miR-375 in cattle

Extra-ovarian expression and activity of growth differentiation factor 9

Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

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