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Published on: September 3, 2021
Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
Lian Liu1, Singareddy Rajareddy, Pradeep Reddy
1Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187, Umeå, Sweden.
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.
Insights
Constitutively active Foxo3a in mouse oocytes causes infertility by inhibiting oocyte growth and follicular development. This occurs through reduced expression of key follicular signaling molecules and increased nuclear localization of p27(kip1).
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
Background:
- Mammalian oocytes play crucial roles in ovarian follicular development and fertility.
- The phosphatidylinositol 3-kinase (PI3K) signaling pathway is implicated in these processes.
Purpose of the Study:
- To investigate the influence of intra-oocyte Foxo3a on follicular development and female fertility.
- To elucidate the molecular mechanisms by which Foxo3a affects oocyte growth and function.
Main Methods:
- Generation of a transgenic mouse model expressing constitutively active Foxo3a in oocytes.
- Assessment of female fertility, oocyte growth, and follicular development in transgenic mice.
- Analysis of gene expression (Bmp15, connexins) and protein localization (p27(kip1)) in oocytes.
Main Results:
- Transgenic female mice exhibited infertility due to retarded oocyte growth, impaired follicular development, and anovulation.
- Constitutively active Foxo3a significantly reduced the expression of bone morphogenic protein 15 (Bmp15), connexin 37, and connexin 43.
- Foxo3a promoted the nuclear localization of p27(kip1) in oocytes, potentially inhibiting oocyte growth.
Conclusions:
- Intra-oocyte Foxo3a acts as a negative regulator of oocyte growth and follicular development.
- Foxo3a's effects are mediated by modulating key signaling molecules and cell cycle inhibitors.
- Findings offer insights into oocyte-derived genetic defects causing anovulation and premature ovarian failure.
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