Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a

Abstract

In recent years, mammalian oocytes have been proposed to have important roles in the orchestration of ovarian follicular development and fertility. To determine whether intra-oocyte Foxo3a, a component of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, influences follicular development and female fertility, a transgenic mouse model was generated with constitutively active Foxo3a expressed in oocytes. We found that the female transgenic mice were infertile, which was caused by retarded oocyte growth and follicular development, and anovulation. Further mechanistic studies revealed that the constitutively active Foxo3a in oocytes caused a dramatic reduction in the expression of bone morphogenic protein 15 (Bmp15), connexin 37 and connexin 43, which are important molecules for the establishment of paracrine and gap junction communications in follicles. Foxo3a was also found to facilitate the nuclear localization of p27 kip1 in oocytes, a cyclin-dependent kinase (Cdk) inhibitor that may serve to inhibit oocyte growth. The results from the current study indicate that Foxo3a is an important intra-oocyte signaling molecule that negatively regulates oocyte growth and follicular development. Our study may therefore give some insight into oocyte-borne genetic aberrations that cause defects in follicular development and anovulation in human diseases, such as premature ovarian failure.

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

“…Previous studies have also demonstrated that constitutively active FoxO3a suppressed Smad pathway activation via downregulation of BMP15 expression in the ovaries from ZP3-FoxO3a Tg mice (11). BMP15 is a growth factor specifically secreted from oocytes, which is important for promoting follicular development (13)(14)(15)(16)(17)(18).…”

“…Previous investigations have indicated that FoxO3a is highly expressed and localized to the nucleus during the dormancy of primordial follicles, then is phosphorylated and exported to the cytoplasm during follicular activation in mice (10). However, the activity of FoxO3a is suppressed in later-growing follicles, indicating that the downregulation of FoxO3a in oocytes may be a prerequisite for the initiation of oocyte growth during follicular activation (11,12).…”

“…Previous studies have demonstrated that BMP15 regulates Smad1/5/8 activity and regulates ovarian follicular development (22)(23)(24). Additionally, Liu et al (11,25) reported that constitutively active FoxO3a expressed in oocytes stimulated downregulation of BMP15 expression and suppressed Smad pathway activation. Furthermore, the BMP15 gene promoter contains FoxO3a binding sites (11,25).…”

“…Additionally, Liu et al (11,25) reported that constitutively active FoxO3a expressed in oocytes stimulated downregulation of BMP15 expression and suppressed Smad pathway activation. Furthermore, the BMP15 gene promoter contains FoxO3a binding sites (11,25). These previous studies indicated that the regulation of FoxO3a during follicular development may be mediated via the BMP15/Smad1/5/8 signaling pathway.…”

Recent advances in the study of genes involved in non-syndromic premature ovarian failure

“…To determine the role of intra-oocyte Foxo3a in the follicular development and female fertility, a transgenic mouse model has been generated, in which the expression of Foxo3a is constitutively active in oocytes in primary and more-developed follicles (Liu et al, 2007). In this study, the expression of Foxo3a in the wild type mice is localized in the nuclei of oocytes in primordial and early primary follicles, and is dramatically downregulated in oocytes of primary and moredeveloped follicles.…”