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Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2007 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 134, no 1, 199-209 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2007. Vol. 134, no 1, 199-209 p.
Identifiers
URN: urn:nbn:se:umu:diva-20766DOI: 10.1242/dev.02667PubMedID: 17164425OAI: oai:DiVA.org:umu-20766DiVA: diva2:209481
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Studies of phosphatidylinositol 3 kinase (PI3K) signaling pathway in mammalian ovarian follicle activation and development
Open this publication in new window or tab >>Studies of phosphatidylinositol 3 kinase (PI3K) signaling pathway in mammalian ovarian follicle activation and development
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intra-oocyte signaling pathways that control oocyte growth and early follicular development are largely unknown. The aim of this thesis was to investigate the regulation and functions of phosphatidylinositol 3 kinase (PI3K) pathway in the oocyte, focusing in the roles of Foxo3a, p27, and Pten (phosphatase and tensin homolog deleted on chromosome ten). The physiological significance of Foxo3a in oocytes had been investigated by generating a transgenic mouse, whereby constitutively active Foxo3a is maintained in oocytes using the oocyte-specific ZP3 (Zona pellucida) promoter. The expression of the constantly active “negative” molecule Foxo3a in mouse oocytes was found to cause retardation of oocyte growth, resulting in a significant reduction in oocyte volume in secondary follicles. The transgenic mice also showed arrested follicular development and were infertile. In addition, when Foxo3a was overexpressed in oocytes of primary follicles, oocyte growth and follicular development were retarded. One of the causes of this phenotype may be the retained expression of the cyclin-dependent kinase (Cdk) inhibitor 1B (Cdkn1b), commonly known as p27kip1 or p27, in the nuclei of oocytes. The role and related mechanisms of p27 in controlling early follicular development and oocyte growth were then investigated using wild-type and p27-deficient (p27-/-) mice, and we demonstrated that (i) p27 suppresses follicle endowment/formation and activation, (ii) p27 induces follicle atresia that occurs prior to sexual maturity, and (iii) the overactivated follicles in p27-/- ovaries are depleted in early adulthood, causing premature ovarian failure (POF). In this thesis, we also provide genetic evidence that in mice with conditional deletion of Pten a major negative regulator of PI3K in oocytes, the entire pool of primordial follicles becomes activated, and subsequently all activated follicles are depleted in young adulthood, causing POF. Further mechanistic studies revealed that loss of Pten in oocytes resulted in elevated Akt signaling, which led to upregulation of both expression and activation of ribosomal protein S6 (rpS6) in oocytes. The results thus show that the mammalian oocyte serves as the headquarters of programming of the occurrence of follicle activation, and that the PI3K pathway of the oocyte governs follicle activation through control of initiation of oocyte growth.

Place, publisher, year, edition, pages
Umeå: Medicinsk kemi och biofysik, 2007. 47 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1117
Keyword
oocyte, follicular development, P13K pathway
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-1378 (URN)978-91-7264-385-7 (ISBN)
Public defence
2007-10-19, KB3A9, KBC huset, Umeå university, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2007-10-01 Created: 2007-10-01 Last updated: 2010-01-08Bibliographically approved
2. The functional roles of the intra-oocyte phosphatidylinositol 3-kinase (PI3K) signaling in controlling follicular development in mice
Open this publication in new window or tab >>The functional roles of the intra-oocyte phosphatidylinositol 3-kinase (PI3K) signaling in controlling follicular development in mice
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The key functions of the mammalian ovary are the production of fertilizable oocytes and thesecretion of steroid hormones. At the time of birth the human ovary is composed of basic unitstermed primordial follicles. Primordial follicles are long-lived structures in the ovary and some ofthem last until the woman reaches menopause. However, the intra-oocyte signaling pathways thatactivate primordial follicles and early follicular development are largely unknown.

In this thesis, the functional roles that the phosphatidylinositol 3-kinase (PI3K) signaling pathwayplays in follicular development were investigated. In vivo approaches using genetically modifiedmouse models were used to determine the functions of several members of the PI3K signalingpathway in oocytes and in follicles. The function of Foxo3a, a substrate of Akt, was investigatedby expressing Foxo3a constitutively in oocytes of primary follicles. We found that continuouslyactive Foxo3a in mouse oocytes caused retardation of oocyte growth, resulting in arrest offollicular development. The functions of p27kip1 (p27) were studied using p27-deficient (p27-/-)mice. It was found that p27 suppresses follicle endowment/formation and activation, and that itinduces follicle atresia. The functions of PI3K signaling in oocytes during follicular activationwere also investigated using conditional mutant mice, by disrupting the Pten in oocytes ofprimordial follicles. We found that, all primordial follicles were prematurely activated due toovergrowth of oocytes and these follicles were depleted in young adulthood, causing prematureovarian failure (POF). At the same time, disruption of the Pten from oocytes of primary follicleshad no effect on activation of primordial follicles, and the follicles developed and maturednormally. The results clearly show that the PI3K pathway in the mammalian oocyte plays a keyrole in follicular activation through control of initiation of oocyte growth and folliculardevelopment.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 51 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1291
Keyword
oocyte, PI3K signaling, primordial follicle
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-26110 (URN)978-91-7264-827-2 (ISBN)
Distributor:
Medicinsk kemi och biofysik, 901 85, Umeå
Public defence
2009-10-30, KB3A9, KBC building, Umeå, 13:00 (English)
Opponent
Supervisors
Projects
Ovary development
Available from: 2009-10-07 Created: 2009-09-24 Last updated: 2009-10-07Bibliographically approved

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