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Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Liu)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Liu)
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Liu)
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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
Place, publisher, year, edition, pages
2008. Vol. 319, no 5863, 611-613 p.
Keyword [en]
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: urn:nbn:se:umu:diva-9169DOI: 10.1126/science.1152257PubMedID: 18239123OAI: oai:DiVA.org:umu-9169DiVA: diva2:148840
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2017-12-14Bibliographically approved
In thesis
1. 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
2. Molecular studies of intra-oocyte phosphatidylinositol 3 kinase (PI3K) signaling pathway in controlling female fertility
Open this publication in new window or tab >>Molecular studies of intra-oocyte phosphatidylinositol 3 kinase (PI3K) signaling pathway in controlling female fertility
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The primordial follicle pool is the main source of developing follicles in the ovary. The length of reproductive life and the onset of menopause are governed by the amount of primordial follicles in the ovary. The genetic factors and molecular mechanisms that maintain the primordial follicles in a dormant and surviving state for the whole of reproductive life are not well understood. The phosphatidylinositol 3 kinase (PI3K) signaling pathways in the oocyte that control oocyte growth and early follicular development are largely unknown. The major aim of this thesis was to investigate the functional role of the intra-oocyte PI3K pathway in the regulation of primordial follicle activation and survival.

 Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a major negative regulator of PI3K. The conditional deletion of Pten in the oocytes of primordial follicles led to the overgrowth of oocytes and activation of the entire pool of primordial follicles. There were higher numbers of activated primordial follicles at postnatal day 8 (PD8) in ovaries lacking PTEN in oocytes; by PD35 all the primordial follicles were activated and all the follicles were depleted by 12 weeks, causing premature ovarian failure (POF). In addition, the rate of follicular death that occurs during sexual maturity is reduced in ovaries that lack PTEN in oocytes. Further mechanistic studies revealed that loss of Pten in oocytes resulted in elevated Akt signaling and upregulation of both expression and activation of ribosomal protein S6 (rpS6). The overactivation of primordial follicles in ovaries that lack PTEN in oocytes is believed to be due to elevated expression and activation of rpS6. PTEN in oocytes is indispensable for the maintenance of primordial follicles in dormancy.

 To study the role of the intra-oocyte PI3K signaling pathway in controlling the survival and maintenance of primordial follicles, 3-phosphoinositide-dependent protein kinase-1 (PDK1) was deleted in oocytes of primordial follicle. The loss of Pdk1 in oocytes led to the depletion of most primordial follicles around the onset of sexual maturity, causing POF during early adulthood. Furthermore, the activation of Akt, p70 S6 kinase 1 (S6K1), and rpS6 was impaired in oocytes that lacked PDK1. The suppressed PDK1–Akt–S6K1–rpS6 signaling in oocytes appears to be responsible for the loss of primordial follicles. The excessive activation of primordial follicles seen in the absence of Pten in oocytes could be reversed by concurrent deletion of Pdk1. In addition, the elevated activation of Akt and S6K1 in the absence of PTEN in oocytes was not observed in PTEN and PDK1 double mutant mice. Similarly, the hyperphosphorylation of rpS6 in oocytes that lack PTEN was prevented in double mutant mice, which was most likely due to downregulation of S6K1 activation. Thus, inactivation of rpS6 in double mutant mice might be the reason for the prevention of excessive primordial follicular activation and survival.

 PTEN and PDK1 in oocytes are essential for the maintenance of quiescence and survival of primordial follicles. The molecular network involving PI3K/PTEN–PDK1 signaling in oocyte controls the survival, loss, and activation of primordial follicles, which together govern reproductive aging and determine the length of reproductive life in females. The results of the above studies indicate that the mammalian oocyte serves as the seat of programming of follicular activation and survival.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 40 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1292
Keyword
Primordial follicles, Oocyte, PI3K
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-26088 (URN)978-91-7264-837-1 (ISBN)
Distributor:
Medicinsk kemi och biofysik, 901 85, Umeå
Public defence
2009-10-23, KB3A9, KBC building, Umeå University, 13:00 (English)
Opponent
Supervisors
Available from: 2009-09-28 Created: 2009-09-23 Last updated: 2010-01-18Bibliographically approved
3. 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
4. Signaling pathways in the development of female germ cells
Open this publication in new window or tab >>Signaling pathways in the development of female germ cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primordial follicles are the first small follicles to appear in the mammalian ovary. Women are born with a fixed number of primordial follicles in the ovaries. Once formed, the pool of primordial follicles serves as a source of developing follicles and oocytes. The first aim of this thesis was to investigate the functional role of the intra-oocyte signaling pathways, especially the phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) pathways in the regulation of primordial follicle activation and survival. We found that a primordial follicle remains dormant when the PI3K and mTORC1 signaling in its oocyte is activated to an appropriate level, which is just sufficient to maintain its survival, but not sufficient for its growth initiation. Hyperactivation of either of these signaling pathways causes global activation of the entire pool of primordial follicles leading to the exhaustion of all the follicles in young adulthood in mice. Mammalian oocytes, while growing within the follicles, remain arrested at prophase I of meiosis. Oocytes within the fully-grown antral follicles resume meiosis upon a preovulatory surge of leutinizing hormone (LH), which indicates that LH mediates the resumption of meiosis. The prophase I arrest in the follicle-enclosed oocyte is the result of low maturation promoting factor (MPF) activity, and resumption of meiosis upon the arrival of hormonal signals is mediated by activation of MPF. MPF is a complex of cyclin dependent kinase 1 (Cdk1) and cyclin B1, which is essential and sufficient for entry into mitosis. Although much of the mitotic cell cycle machinery is shared during meiosis, lack of Cdk2  in mice leads to a postnatal loss of all oocytes, indicating that Cdk2 is important for oocyte survival, and probably oocyte meiosis also. There have been conflicting results earlier about the role of Cdk2 in metaphase II arrest of Xenopus  oocytes. Thus the second aim of the thesis was to identify the specific Cdk that is essential for mouse oocyte meiotic maturation. We generated mouse models with oocytespecific deletion of Cdk1  or Cdk2  and studied the specific requirements of Cdk1 and Cdk2 during resumption of oocyte meiosis. We found that only Cdk1 is essential and sufficient for the oocyte meiotic maturation. Cdk1 does not only phosphorylate the meiotic phosphoproteins during meiosis resumption but also phosphorylates and suppresses the downstream protein phosphatase 1, which is essential for protecting the Cdk1 substrates from dephosphorylation.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 41 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1649
Keyword
ovary, primordial follicle, activation, mTORC₁, PI₃K, oocyte maturation, MPF, Cdk₁
National Category
Biochemistry and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-88309 (URN)978-91-7601-056-3 (ISBN)
Public defence
2014-05-23, KB3B1, KBC-huset, Linnaeus väg 6, Umeå, 09:30 (English)
Opponent
Supervisors
Available from: 2014-04-30 Created: 2014-04-30 Last updated: 2014-05-05Bibliographically approved

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