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.
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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)