Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth.
In mammals, oocytes are packaged into compact structures-primordial follicles-which remain inert for prolonged intervals until individual follicles resume growth via a process known as primordial follicle activation. Here we show that the phosphoinositide 3-kinase (PI3K) signalling pathway controls primordial follicle activation through the forkhead transcription factor Foxo3. Within oocytes, Foxo3 is regulated by nucleocytoplasmic shuttling. Foxo3 is imported into the nucleus during primordial follicle assembly, and is exported upon activation. Oocyte-specific ablation of Pten resulted in PI3K-induced Akt activation, Foxo3 hyperphosphorylation, and Foxo3 nuclear export, thereby triggering primordial follicle activation, defining the steps by which the PI3K pathway and Foxo3 control this process. Inducible ablation of Pten and Foxo3 in adult oocytes using a new tool for genetic analysis of the germline, Vasa-Cre(ERT2), showed that this pathway functions throughout life. Thus, a principal physiologic role of the PI3K pathway is to control primordial follicle activation via Foxo3.
John
George B
GB
Department of Pathology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9072, USA.
Gallardo
Teresa D
TD
Shirley
Lane J
LJ
Castrillon
Diego H
DH
D000818:Animals; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051379:Mice; D009865:Oocytes / Q000254:growth & development*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse