Changes in expression of bone morphogenetic proteins (BMPs), their receptors and inhibin co-receptor betaglycan during bovine antral follicle development: inhibin can antagonize the suppressive effect of BMPs on thecal androgen production

Abstract

We reported previously that bone morphogenetic proteins (BMPs) potently suppress CYP17 expression and androgen production by bovine theca interna cells (TC) in vitro. In this study, real-time PCR was used to analyse gene expression in TC and granulosa cell (GC) layers from developing bovine antral follicles (1-18 mm). Abundance of mRNA transcripts for four BMPs (BMP2, BMP4, BMP6, and BMP7) and associated type I (BMPR1A, BMPR1B, ACVR1 and ACVR1B) and type II (BMPR2, ACVR2A and ACVR2B) receptors showed relatively modest, though significant, changes during follicle development. BMP2 was selectively expressed in GC, while BMP6, BMP7 and betaglycan (TGFBR3) were more abundant in TC. Abundance of betaglycan mRNA (inhibin co-receptor) in TC increased progressively (fivefold; P!0.001) as follicles grew from 1-2 to 9-10 mm. This suggests a shift in thecal responsiveness to GC-derived inhibin, produced in increasing amounts as follicles achieve dominance. This prompted us to investigate whether inhibin can function as a physiological antagonist of BMP action on bovine TC in vitro, in a manner comparable to that for activin signalling. BMP4, BMP6 and BMP7 abolished LH-induced androstenedione secretion and suppressed CYP17 mRNA O200-fold (P!0.001), while co-treatment with inhibin-A reversed the suppressive action of BMP in each case (P!0.001). Results support a physiological role for granulosa-derived inhibin as an antagonist of BMP action on thecal androgen synthesis. A shift in intrafollicular balance between thecal BMP signalling (inhibitory for androgen synthesis) and betaglycan-dependent inhibin signalling (stimulatory for androgen synthesis) accords with the physiological requirement to deliver an adequate supply of aromatase substrate to GC of developing follicles.

Characterization of microRNAs differentially expressed during bovine follicle development

“…Many of the signaling pathways overrepresented by these targets corresponded to growth factors putatively involved in follicular cell proliferation and steroidogenesis and prevention of premature luteinization including HGF, IGF1, TGFb, estrogen, neurotropin/TRK, PEDF, and NGF (Parrott et al 1993, Salas et al 2006, Glister et al 2010, Mani et al 2010, Garcia-Rudaz et al 2011, Chuderland et al 2013 and others involved in oocyte maturation including neuregulin, GDNF, and EGF (Conti et al 2006, Noma et al 2011, Linher-Melville & Li 2013, the fine-tune regulation of which is of key importance during the final stages of follicle development. Also present were several core cell cycle regulatory pathways (cell cycle regulation by BTG family proteins, estrogen-mediated S phase entry, and G1/S checkpoint regulation), a finding which is consistent with the notion that the development of the dominant follicle involves a substantial decrease in granulosa cell proliferation (Lussier et al 1987, Gaytan et al 1996.…”

Expression and localization of bone morphogenetic protein6 (BMP6) in the corpus luteum during different stages of estrous cycle in the buffalo (Bubalus bubalis)

“…In the ovary, investigations on BMPs are mainly studied in the follicle of rat (Erickson & Shimasaki, 2003), cow (Glister et al, 2010) and ewe (Juengel et al, 2006). Except a solitary report by Erickson & Shimasaki (2003) on rat, no study could be found on BMPs in the CL.…”

“…(Ferrara et al, 2003;Kaczmarek et al, 2005;Bramley et al, 2005;Otrock et al, 2007). Among the ovarian factors, members of the TGF-β super family have a biological role in the folliculogenesis in the cow (Knight & Glister, 2006;Glister et al, 2010).…”

“…Additionally, the BMP system was shown to play a crucial role in folliculogenesis in humans (Shi et al, 2009;Shi et al, 2010;Shi et al, 2011). Of the BMPs, BMP6 is highly expressed in the theca cell layer in the ovarian follicles and CL of rat (Shimasaki et al, 2004) and cow (Glister et al, 2010). Until now, no published information is available regarding BMP6 expression and localization in various stages of development of CL in buffalos.…”

The local regulation of folliculogenesis by members of the transforming growth factor superfamily and its relevance for advanced breeding programmes

“…The oocyte also produces BMP6 in sheep (Juengel et al, 2006b) and cattle (Hussein et al, 2005) but BMP6 did not induce cell proliferation in sheep (Juengel et al, 2006b) and had a small effect on bovine mural granulosa cells (Glister et al, 2004) and no effect on cumulus cells (Gilchrist et al, 2006). In cattle, granulosa and theca cells from small antral follicles (1-4 mm in diameter) produce BMP2, BMP4, BMP6 and BMP7 (Glister et al, 2010) whereas in sheep, as determined by in situ hybridisation, only granulosa cells of atretic follicles express BMP2. The other BMPs were not expressed by the granulosa or theca cells, although BMP4 was produced in ovarian stroma cells surrounding some follicles.…”