The Cooperative Effect of Growth and Differentiation Factor-9 and Bone Morphogenetic Protein (BMP)-15 on Granulosa Cell Function Is Modulated Primarily through BMP Receptor II

Abstract

Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15, GDF9B) are oocyte-derived proteins essential for the growth and function of ovarian follicles. Moreover, ovine (o) GDF9 and oBMP15 cooperate to increase both (3)H-thymidine incorporation and alpha-inhibin production and to inhibit progesterone production by rat or ovine granulosa cells. Although the receptors through which these proteins act individually have been determined, the receptor(s) involved in mediating the cooperative effects of GDF9 and BMP15 is (are) unknown. In this study, the effects of the extracellular domains of the types I and II TGFbeta receptors on (3)H-thymidine incorporation by rat granulosa cells stimulated by oGDF9 and oBMP15 were investigated. Stimulation of (3)H-thymidine incorporation was completely blocked by the BMP receptor II (BMPRII) extracellular domain but unaffected by any other type II or any type I receptor. These results suggest that the initial interaction of oGDF9 and oBMP15 is with BMPRII and that a type I receptor is either recruited or already associated with BMPRII to mediate the cooperative effects of these growth factors.

Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation

“…Similarly, BMP15 inhibits the production of progesterone induced by 8-bromo-AMPc in follicular cells [45]. BMP15 has been shown to activate the Smad 1/5/8 pathway through BMPR2 and ALK6 [29], with BMPR2 having the greatest effect on BMP15 suppression of FSH-induced progesterone production [28]. Moreover, a recent study reports the co-operative effects of GDF9 and BMP15, modulated through BMPR2, on inhibition of FSH-stimulated progesterone production [28] that reinforces our results.…”

“…Following ligand binding, TGFβRI or BMPRIB recruits the BMPR2 that results in phosporylation of the type 1 receptor, which in turn activates the intracellular-signal-mediated (Smad) proteins [16,26,27]. Recently, the BMPR2 has been identified as the receptor that primarily modulates the cooperative effects of GDF9 and BMP15 on rat granulosa cells function, with BMPR2 having the greatest effect on BMP15 suppression of FSHinduced progesterone production [28]. Furthermore, the type 2 receptor is appointed as the most effective in BMP15 bioactivity [29].…”

Using sheep lines with mutations in single genes to better understand ovarian function

“…Members of the TGFB superfamily typically interact with a receptor complex composed of two types (type 1 and 2) of membrane-bound serine-threonine kinases (de Caestecker 2004, ten Dijke & Hill 2004. Both GDF9 and BMP15 use BMPR2 for the type 2 receptor (Vitt et al 2002, Edwards et al 2008. BMP15 signals through BMPR1B as its type 1 receptor , Pulkki et al 2012 with GDF9 signalling through the TGFBR1 receptor (Mazerbourg et al 2004).…”

“…These include, but are not limited to, a better understanding of the biologically active forms of BMP15 and GDF9 produced by the oocyte in vivo. Analysis of GDF9 and BMP15, in follicular fluid, oocyte lysates and from cell lines expressing GDF9 or BMP15, indicates that GDF9 and BMP15 may be secreted as a complex mix of forms (Liao et al 2003, McNatty et al 2006b, Edwards et al 2008, McIntosh et al 2008, Lin et al 2012. New data are emerging regarding the effects of post-translational modifications on the activity of GDF9 and BMP15 (McMahon et al 2008) and the role of sequence in the proregion in regulating activity of the mature region.…”

Inhibition of oocyte growth factors in vivo modulates ovarian folliculogenesis in neonatal and immature mice

“…GDF9 activates the TGFB-type signaling pathway by using the activin receptor-like kinase-5 (ALK5; Mazerbourg et al 2004, Kaivo-Oja et al 2005 and BMP type II receptor (BMPR2; Vitt et al 2002). Cooperative signaling by GDF9 and BMP15 is also mediated through BMPR2 (Edwards et al 2007). BMP15 utilizes the ALK6 and the BMP pathway (SMAD1/5/8) to mediate responses (Moore et al 2003).…”