Abstract
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.
Highlights
In women, the 300,000–400,000 ovarian primordial follicles at menarche serve as the source of fertilizable ova for the entire duration of reproductive life [1]
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]
As an indicator of Akt activity, the phosphorylation of Tsc2, which is an Akt substrate, was found to be elevated in PtenloxP/loxP; zona pellucida 3 (Zp3)-Cre+ oocytes compared to control PtenloxP/loxP oocytes. These results suggest that there is enhanced activation of phosphatidylinositol 3-kinase (PI3K)–Akt signaling in oocytes of growing follicles upon deletion of Pten in PtenloxP/loxP; Zp3-Cre+ mice
Summary
The 300,000–400,000 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. 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]. 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 functions as a major negative regulator of PI3K [5]
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