Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation

PLOS ONE, Jul 2009

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.

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Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation

et al. (2009) Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation. PLoS ONE 4(7): e6186. doi:10.1371/journal.pone.0006186 Oocyte-Specific Deletion of Pten in Mice Reveals a Stage- Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation Krishna Jagarlamudi 0 Lian Liu 0 Deepak Adhikari 0 Pradeep Reddy 0 Annika Idahl 0 Ulrika Ottander 0 Eva Lundin 0 Kui Liu 0 David E. Clapham, Harvard Medical School, United States of America 0 1 Department of Medical Biochemistry and Biophysics, Umea University, Umea , Sweden, 2 Clinical Science/Obstetrics and Gynecology, Umea University, Umea , Sweden, 3 Medical Biosciences/Pathology, Umea University, Umea , Sweden, 4 Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University , Jinan , China , 5 Institute of Immunology, School of Medicine, Shandong University , Jinan , China 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. - Funding: This work was supported by grants from the Swedish Research Council, the Swedish Cancer Foundation, the Young Researcher Award of Umea University, Sweden, the Lions Cancer Research Foundation in Norrland, Sweden, the Novo Nordisk Foundation, Denmark (K.L.), the Cutting-Edge Research Grant from the County Council of Vasterbotten, Sweden (E.L.), and the Stiftelsen J. C. Kempes Minnes Stipendiefond (K.J). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. In women, the 300,000400,000 ovarian primordial follicles at menarche serve as the source of fertilizable ova for the entire duration of reproductive life [1]. In order to ensure the proper length of reproductive life, the majority of primordial follicles remain in a dormant state, and only limited numbers of them are recruited into the growing follicle pool through follicular activation. Menopause occurs when the pool of primordial follicles has become exhausted [13]. Recently, studies from our research group have suggested that the phosphatidylinositol 3-kinase (PI3K) signaling pathway in oocytes plays an important role in oocyte growth during early follicular development [4]. The PI3K pathway is a fundamental signaling pathway for regulation of cell proliferation, survival, migration, and metabolism [5]. PI3Ks are lipid kinases that phosphorylate the 39-OH group on the inositol ring of inositol phospholipids. PTEN (phosphatase and tensin homolog deleted on chromosome ten), a lipid phosphatase, dephosphorylates the inositol phospholipids and thus functions as a major negative regulator of PI3K [5]. We have shown that deletion of the Pten gene from mouse oocytes of primordial follicles using transgenic mice expressing Cre recombinase mediated by the growth differentiation factor 9 (Gdf-9) promoter, results in excessive activation of the entire pool of primordial follicles, which in turn leads to premature depletion of all primordial follicles [6]. However, such mutant mice show normal ovulation and normal litter size in young adulthood before their ovarian follicles are depleted [6]. The current study was designed to investigate the role of PTEN/PI3KAkt signaling in oocytes of p (...truncated)


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Krishna Jagarlamudi, Lian Liu, Deepak Adhikari, Pradeep Reddy, Annika Idahl, Ulrika Ottander, Eva Lundin, Kui Liu. Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation, PLOS ONE, 2009, 7, DOI: 10.1371/journal.pone.0006186