title: 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.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-90187, Umeå, Sweden.
authors.forename: Lian
authors.initials: L
authors.lastname: Liu
authors.forename: Singareddy
authors.initials: S
authors.lastname: Rajareddy
authors.forename: Pradeep
authors.initials: P
authors.lastname: Reddy
authors.forename: Chun
authors.initials: C
authors.lastname: Du
authors.forename: Krishna
authors.initials: K
authors.lastname: Jagarlamudi
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: David
authors.initials: D
authors.lastname: Gunnarsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Selstam
authors.forename: Karin
authors.initials: K
authors.lastname: Boman
authors.forename: Kui
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007247:Infertility, Female; D051379:Mice; D008822:Mice, Transgenic; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000196:embryology* / Q000502:physiology*
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse