Abstract
Primordial follicle (PF) pool determines the availability of follicles for ovulation in all mammals. Premature depletion of the PF reserve leads to subfertility or infertility. Bone morphogenetic protein 2 (BMP2) promotes PF formation by facilitating oocyte and granulosa cell development. Estradiol-17β (E2) upregulates PF formation in developing hamster ovaries. However, if BMP2 mediates E2 effect is not known. We hypothesize that E2 facilitates the effect of BMP2 on somatic to granulosa cell transition. BMP2 and E2 together significantly upregulated the percentage of PFs in hamster fetal ovaries in vitro compared with either of the treatments alone. E2 also promoted BMP2 expression in vivo. Inhibition of BMP2 receptors suppressed E2-stimulation of PF formation while knockdown of BMP2 in vitro significantly suppressed the E2 effect. In contrast, estrogen receptor blocker did not affect BMP2 action. Inhibition of the activity of E2 or BMP2 receptors, either alone or combined during the last two days of the culture (C6-C8) resulted in a significant decrease in PF formation by C8, suggesting that both BMP2 and E2 action is essential for somatic cell differentiation for PF formation. Together, the results suggest that E2 activates BMP2-BMPR system leading to the formation of primordial follicles.
Highlights
Successful follicular development is essential for reproduction[1]
ALK2/3 inhibitor could suppress (p < 0.05) the stimulatory effect of E2 (p < 0.05) or E2 plus Bone morphogenetic protein 2 (BMP2) (Fig. 2) on Primordial follicle (PF) formation, small but significantly higher PF formation was still evident compared to untreated control ovaries (Fig. 2), suggesting that at least part of the E2 effect might be mediated by the activities of bone morphogenetic protein receptors (BMPRs)
The results of the present study show that either BMP2 or E2 can promote the formation of PFs; BMP2 appears to mediate the effect of E2 on the formation of primordial follicles (Fig. 9)
Summary
Successful follicular development is essential for reproduction[1]. During female gametogenesis, oocyte development is supported by surrounding somatic cells[2]. Aromatase expression is detected in the ovary from E13, and increase in serum E2 is evident in neonatal hamsters before the formation PFs on post-natal day 8 (P8)[18]. While BMP4 does not affect PF formation in 4-day old rat ovaries in culture, it accelerates primordial to primary follicle transition[17]. The expression of BMP2 is present in developing ovaries during oocyte development and PF formation in the mouse[32], human[31] and hamster[8]. BMPs utilize membrane bound bone morphogenetic protein receptors (BMPRs) such as ALK2, ALK3 and ALK6 to mediate their effect Both ALK3 and ALK6 are expressed in developing hamster ovary before and around the time of PF formation[33]. GDF9 promotes PF formation[38]
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