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Phosphorylation and inactivation of glycogen synthase kinase-3 by soluble kit ligand in mouse oocytes during early follicular development.
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: 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.

Place, publisher, year, edition, pages
2007. Vol. 38, no 1-2, 137-146 p.
Keyword [en]
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: urn:nbn:se:umu:diva-16507DOI: 10.1677/jme.1.02027PubMedID: 17242176OAI: diva2:156180
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-03-30Bibliographically 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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1117
oocyte, follicular development, P13K pathway
Research subject
Medical Biochemistry
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)
Available from: 2007-10-01 Created: 2007-10-01 Last updated: 2010-01-08Bibliographically approved

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Guo, YongzhiBoman, KarinLundin, EvaOttander, UlrikaSelstam, GunnarLiu, Kui
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Department of Medical Biochemistry and BiophysicsDepartment of Radiation SciencesObstetrics and GynaecologyDepartment of Molecular Biology (Faculty of Medicine)
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Journal of Molecular Endocrinology

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