Bone morphogenetic protein-4 interacts with activin and GnRH to modulate gonadotrophin secretion in LβT2 gonadotrophs

Nicol, Linda; Faure, Marie-Odile; McNeilly, J R; Fontaine, Joël; Taragnat, Catherine; McNeilly, A. S.

doi:10.1677/joe-07-0542

Cited by 43 publications

(40 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…In addition to the negative regulation of gonadotropin production by PTGFRN, BMP signaling has also been shown to interfere with hormone production in pituitary gonadotrophs (42,43 Figure 4G). Moreover, testicular expression of the Leydig cell marker CYP17A1 was reduced by 35% ( Figure 4H).…”

Section: Mir-7 Targets Ptgfrn and Glg1 Regulate Expression And Secretmentioning

confidence: 99%

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility

Ahmed¹,

LaPierre²,

Gasser³

et al. 2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of mir-7a2 causes infertility, with low levels of gonadotropic and sex steroid hormones, small testes or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling

show abstract

“…However, modulation of FSHB transcription by BMPs varies between species (Visser & Themmen 2014). In murine primary pituitary cells, various BMPs including BMP15, BMP7, BMP6, and BMP4 stimulate FSHB transcription (Huang et al 2001, Otsuka & Shimasaki 2002, Nicol et al 2008, whereas BMP6 and BMP4 inhibit FSHB transcription in ovine cells (Faure et al 2005). In accordance with the stimulatory effect of BMPs in murine primary pituitary cells, it has been shown that BMP2 acts synergistically with Activin A to regulate FSHb expression in LbT2 cells (Lee et al 2007, Wang et al 2014.…”

Section: Discussionmentioning

confidence: 92%

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

Jung

Ahn

Shim

et al. 2014

Journal of Endocrinology

View full text Add to dashboard Cite

Activins and bone morphogenetic proteins (BMPs) share activin type 2 signaling receptors but utilize different type 1 receptors and Smads. We designed AB215, a potent BMP2-like Activin A/BMP2 chimera incorporating the high-affinity type 2 receptor-binding epitope of Activin A. In this study, we compare the signaling properties of AB215 and BMP2 in HEK293T cells and gonadotroph LbT2 cells in which Activin A and BMP2 synergistically induce FSHb. In HEK293T cells, AB215 is more potent than BMP2 and competitively blocks Activin A signaling, while BMP2 has a partial blocking activity. Activin A signaling is insensitive to BMP pathway antagonism in HEK293T cells but is strongly inhibited by constitutively active (CA) BMP type 1 receptors. By contrast, the potencies of AB215 and BMP2 are indistinguishable in LbT2 cells and although AB215 blocks Activin A signaling, BMP2 has no inhibitory effect. Unlike HEK293T, Activin A signaling is strongly inhibited by BMP pathway antagonism in LbT2 cells but is largely unaffected by CA BMP type 1 receptors. BMP2 increases phospho-Smad3 levels in LbT2 cells, in both the absence and the presence of Activin A treatment, and augments Activin A-induced FSHb. AB215 has the opposite effect and sharply decreases basal phospho-Smad3 levels and blocks Smad2 phosphorylation and FSHb induction resulting from Activin A treatment. These findings together demonstrate that while AB215 activates the BMP pathway, it has opposing effects to those of BMP2 on FSHb induction in LbT2 cells apparently due to its ability to block Activin A signaling. Key Words" transforming growth factor beta (TGFb)" activin " bone morphogenetic protein (BMP)" protein structure " signal transduction

show abstract

Bone morphogenetic protein-4 interacts with activin and GnRH to modulate gonadotrophin secretion in LβT2 gonadotrophs

Cited by 43 publications

References 39 publications

Extra-ovarian expression and activity of growth differentiation factor 9

Extra-ovarian expression and activity of growth differentiation factor 9

Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility

Regulation of FSHβ induction in LβT2 cells by BMP2 and an Activin A/BMP2 chimera, AB215

Contact Info

Product

Resources

About