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Studies of phosphatidylinositol 3 kinase (PI3K) signaling pathway in mammalian ovarian follicle activation and development
Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1117
Keyword [en]
oocyte, follicular development, P13K pathway
Research subject
Medical Biochemistry
URN: urn:nbn:se:umu:diva-1378ISBN: 978-91-7264-385-7OAI: diva2:140811
Public defence
2007-10-19, KB3A9, KBC huset, Umeå university, Umeå, 13:00 (English)
Available from: 2007-10-01 Created: 2007-10-01 Last updated: 2010-01-08Bibliographically approved
List of papers
1. Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.
Open this publication in new window or tab >>Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.
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2007 (English)In: Journal of Molecular Endocrinology, ISSN 0952-5041, Vol. 38, no 1-2, 137-146 p.Article in journal (Refereed) Published
Abstract [en]

Communication between mammalian oocytes and their surrounding granulosa cells through the Kit-Kit ligand (KL, or stem cell factor, SCF) system has been shown to be crucial for follicular development. Our previous studies (Reddy et al. 2005, Liu et al. 2006) have indicated that the intra-oocyte KL-Kit-PI3 kinase (PI3K)-Akt-Foxo3a cascade may play an important role in follicular activation and early development. In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes. Also, treatment of cultured mouse oocytes with soluble KL not only leads to increased Akt kinase activity in the oocytes, which can phosphorylate recombinant GSK-3 in vitro, but also leads to phosphorylation of oocyte GSK-3alpha and GSK-3beta, which can result in the inactivation of GSK-3 function in oocytes. In addition, we have shown that the regulation of GSK-3alpha and GSK-3beta in cultured oocytes by soluble KL is accomplished through PI3K, since the PI3K-specific inhibitor LY294002 completely abolished the KL-induced phosphorylation of GSK-3alpha and GSK-3beta. Moreover, blockage of the Kit signaling pathway by a Kit function-blocking antibody, ACK2, resulted in reduced phosphorylation of GSK-3. Taken together, our data suggest that the cascade from granulosa cell-derived KL to Kit-PI3K-Akt-GSK-3 in oocytes may take part in regulation of oocyte growth and early ovarian follicular development.

Animals, Female, Glycogen Synthase Kinase 3/*antagonists & inhibitors/metabolism, Mice, Mice; Inbred C57BL, Oocytes/*enzymology, Ovarian Follicle/*enzymology, Phosphorylation, Proto-Oncogene Proteins c-akt/physiology, Stem Cell Factor/*physiology
urn:nbn:se:umu:diva-16507 (URN)10.1677/jme.1.02027 (DOI)17242176 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-03-30Bibliographically approved
2. 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.

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: 2011-03-30Bibliographically approved
3. 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, Vol. 21, no 9, 2189-2202 p.Article in journal (Refereed) Published
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
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: 2009-10-07Bibliographically approved
4. 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, Vol. 319, no 5863, 611-613 p.Article in journal (Refereed) Published
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
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: 2014-04-30Bibliographically approved

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