title: Cell autonomous phosphoinositide 3-kinase activation in oocytes disrupts normal ovarian function through promoting survival and overgrowth of ovarian follicles.
abstract: In this study, we explored the effects of oocytic phosphoinositide 3-kinase (PI3K) activation on folliculogensis by generating transgenic mice, in which the oocyte-specific Cre-recombinase induces the expression of constitutively active mutant PI3K during the formation of primordial follicles. The ovaries of neonatal transgenic (Cre+) mice showed significantly reduced apoptosis in follicles, which resulted in an excess number of follicles per ovary. Thus, the elevation of phosphatidylinositol (3,4,5)-trisphosphate levels within oocytes promotes the survival of follicles during neonatal development. Despite the increase in AKT phosphorylation, primordial follicles in neonatal Cre+ mice remained dormant demonstrating a nuclear accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). These primordial follicles containing a high level of nuclear PTEN persisted in postpubertal females, suggesting that PTEN is the dominant factor in the maintenance of female reproductive lifespan through the regulation of primordial follicle recruitment. Although the oocytic PI3K activity and PTEN levels were elevated, the activation of primordial follicles and the subsequent accumulation of antral follicles with developmentally competent oocytes progressed normally in prepubertal Cre+ mice. However, mature Cre+ female mice were anovulatory. Because postnatal day 50 Cre+ mice released cumulus-oocyte complexes with developmentally competent oocytes in response to super-ovulation treatment, the anovulatory phenotype was not due to follicular defects but rather endocrine abnormalities, which were likely caused by the excess number of overgrown follicles. Our current study has elucidated the critical role of oocytic PI3K activity in follicular function, as well as the presence of a PTEN-mediated mechanism in the prevention of immature follicle activation.
authors.affiliation: Division of Reproductive Science in Medicine (S.K., K.E., M.H.C., M.R., J.Z., K.A.W., T.K.W.), Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Department of Molecular and Cellular Biochemistry (V.A.S., T.K.), The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Kim
authors.forename: Katherine
authors.initials: K
authors.lastname: Ebbert
authors.forename: Marilia H
authors.initials: MH
authors.lastname: Cordeiro
authors.forename: Megan
authors.initials: M
authors.lastname: Romero
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Vanida Ann
authors.initials: VA
authors.lastname: Serna
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Whelan
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Woodruff
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000254:growth & development* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases