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The functional roles of the intra-oocyte phosphatidylinositol 3-kinase (PI3K) signaling in controlling follicular development in mice
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics. (Kui Liu)
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 [en]
oocyte, PI3K signaling, primordial follicle
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-26110ISBN: 978-91-7264-827-2 (print)OAI: oai:DiVA.org:umu-26110DiVA: diva2:236712
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
List of papers
1. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
Open this publication in new window or tab >>Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a
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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.

Identifiers
urn:nbn:se:umu:diva-20766 (URN)10.1242/dev.02667 (DOI)17164425 (PubMedID)
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2017-12-13Bibliographically approved
2. p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice
Open this publication in new window or tab >>p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice
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2007 (English)In: Molecular Endocrinology, ISSN 0888-8809, E-ISSN 1944-9917, Vol. 21, no 9, 2189-2202 p.Article in journal (Refereed) Published
Keyword
Animals, Animals; Newborn, Cyclin-Dependent Kinase Inhibitor p27/deficiency/genetics/*physiology, Female, Mice, Mice; Inbred C57BL, Mice; Knockout, Ovarian Follicle/*metabolism, Ovary/*embryology/*growth & development, Rabbits
Identifiers
urn:nbn:se:umu:diva-6623 (URN)10.1210/me.2007-0172 (DOI)17565040 (PubMedID)
Available from: 2007-12-16 Created: 2007-12-16 Last updated: 2017-12-14Bibliographically approved
3. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool
Open this publication in new window or tab >>Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool
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2008 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 319, no 5863, 611-613 p.Article in journal (Refereed) Published
Keyword
1-Phosphatidylinositol 3-Kinase/metabolism, Animals, Female, Follicular Atresia, Mice, Mice; Transgenic, Oocytes/cytology/growth & development/*physiology, Organ Size, Ovarian Failure; Premature/physiopathology, Ovarian Follicle/cytology/*physiology, Ovary/anatomy & histology/physiology, Ovulation, PTEN Phosphohydrolase/genetics/*physiology, Phosphorylation, Protein Kinases/metabolism, Ribosomal Protein S6/metabolism, Signal Transduction
Identifiers
urn:nbn:se:umu:diva-9169 (URN)10.1126/science.1152257 (DOI)18239123 (PubMedID)
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2017-12-14Bibliographically approved
4. Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation
Open this publication in new window or tab >>Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation
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2009 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, e6186- p.Article in journal (Refereed) Published
Abstract [en]

Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.

Identifiers
urn:nbn:se:umu:diva-26301 (URN)10.1371/journal.pone.0006186 (DOI)19587782 (PubMedID)
Available from: 2009-10-07 Created: 2009-10-05 Last updated: 2017-12-13Bibliographically approved

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