Dynamic regulation of pituitary mRNAs for bone morphogenetic protein (BMP) 4, BMP receptors, and activin/inhibin subunits in the ewe during the estrous cycle and in cultured pituitary cells

Abstract

Recently, bone morphogenetic protein (BMP) 4 has been shown to inhibit FSH secretion in ewe. The detection of BMP4 mRNA and BMP receptors in the pituitary suggests that BMP4 can exert paracrine actions on FSH production. This work aimed at determining whether BMP4 and/or BMP receptor mRNA as well as activin/inhibin subunit mRNA fluctuates during the estrous cycle when FSHb mRNA and FSH release changed. The estrous cycles of ewes were synchronized with progestagen sponges. Ewes were killed in late follicular stage (nZ5), before the secondary FSH surge (nZ4), and in luteal phase (nZ4). Using quantitative reverse transcription-PCR, we showed that the levels of mRNA for BMP4, BMP receptor, the inhibitor of differentiation 2 (Id2), a target gene of BMP4, and noggin did not change significantly across the estrous cycle.In contrast, the level of activin bB mRNA and the percentage of immunoreactive cells for activin bB-subunit were higher before the secondary surge of FSH compared to other groups. In ewe pituitary cell cultures, activin, GnRH, or estradiol17b (E 2 ) did not significantly affect the levels of BMP4, BMP receptor, and Id2 mRNA. E 2 , but not GnRH, increased the level of activin bB mRNA. Moreover, the in vitro FSH release was not modified by noggin, a BMP antagonist. In contrast, SB431542, an inhibitor of activin pathway, inhibited FSH release. Collectively, our data showed that pituitary BMP4 would not play a crucial role in the regulation of FSH production during the estrous cycle, whereas local activin B would be a major stimulus of FSH synthesis necessary for the secondary FSH surge.

Control of the Ovarian Cycle of the Sheep

“…Similarly, pituitary inhibin-A expression did not change in response to variations in GnRH that stimulated FSH secretion, 187 and follistatin concentrations actually increased in response to a GnRH treatment that increased FSH release. The most consistent in vivo evidence comes from the strong positive correlations of FSHβ mRNA with the mRNA levels of three activin receptors 185 and of activin-βB (but not βA) 186 at the time of the second FSH surge. The most consistent in vivo evidence comes from the strong positive correlations of FSHβ mRNA with the mRNA levels of three activin receptors 185 and of activin-βB (but not βA) 186 at the time of the second FSH surge.…”

“…187 There has been some recent work on the possible roles of bone morphogenetic proteins (BMPs) that are members of the same large protein family as activin and are found in the pituitary, but support for an important role for these peptides is not compelling. 186 Thus, it appears at this time that activin is the only pituitary paracrine factor important to changes in FSH synthesis and secretion during the ovine estrous cycle. 189 However, the inhibitory effects of BMP2 and BMP6 were observed at only one of the doses tested in the latter study.…”

“…Although several studies have demonstrated that inhibin can decrease FSH release in vitro, 1 no changes have been observed in hypophysial mRNA for inhibin receptors 185 or in local levels of mRNA or protein for the α-subunit of inhibin 186 in the pituitary at times during the estrous cycle when FSH secretion varies markedly. Although several studies have demonstrated that inhibin can decrease FSH release in vitro, 1 no changes have been observed in hypophysial mRNA for inhibin receptors 185 or in local levels of mRNA or protein for the α-subunit of inhibin 186 in the pituitary at times during the estrous cycle when FSH secretion varies markedly.…”

Normal gonadotropin production and fertility in gonadotrope-specific Bmpr1a knockout mice

“…Activin B is generally regarded as the primary autocrine/paracrine stimulator of Fshb transcription (Corrigan et al , 1991, Sallon et al , 2010). Consistent with this idea, treatment of isolated gonadotropes from wild-type mice with a small molecule inhibitor (SB431542) (Inman et al , 2002) of the known activin B type I receptors (ACVR1B and ACVR1C) (Tsuchida et al , 2004, Bernard et al , 2006) dramatically reduced Fshb expression (Fig.…”

Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells

“…On the other hand, BMP-4 and BMP-6 decreased both basal and activin-stimulated FSHβ mRNA levels and FSH release in ewe pituitary cells (Faure et al, 2005). This discrepancy of BMP responsiveness could be due to species differences, different genetic background (Young et al, 2008) or to estrous cycle status (Sallon et al, 2010). The differential expression patterns of BMP receptors between mixed primary pituitary cell cultures in ewe and mouse LβT2 cells may also be involved in the activation of diverged signaling pathways and/or intracellular components (Nicol et al, 2008).…”