PI3K Signaling via Foxo3 in Primordial Follicle Activation.

Primordial follicle activation (PFA) is the irreversible, metered process by which primordial follicles are selected from the reserve pool. PFA is a delicately balanced and tightly regulated process ensuring that some number of growing follicles is available during each estrus/menstrual cycle. At the same time, PFA limits the number of growing follicles, thereby avoiding premature depletion of primordial follicles and early reproductive senescence. Because the mechanisms regulating PFA in effect balance fertility with reproductive senescence, their elucidation is of fundamental importance for understanding the biological basis of female infertility and early menopause syndromes such as primary ovarian insufficiency. We initially identified the forkhead transcription factor Foxo3 as a critical regulator and suppressor of this process. Foxo3 knockout mice undergo global activation as soon as primordial follicle assembly is completed. More recently, we have shown that Foxo3 serves as an active molecular switch within the oocyte. During oogenesis, the Foxo3 protein is initially cytoplasmic, but is imported into the oocyte nucleus coincident with the completion of primordial follicle assembly. The Foxo3 protein remains within the nucleus throughout life until activation, when the protein is exported to the cytoplasm. This process is regulated by the phosphoinositide 3-kinase (PI3K) signalling pathway. PI3K-induced Akt activation promotes Foxo3 hyperphosphorylation and nuclear export, thereby triggering primordial follicle activation. Inducible genetic ablation of pathway components including Foxo3 in adult oocytes showed that this pathway functions throughout life. Thus, a principal physiologic role of the PI3K pathway is to control primordial follicle activation via Foxo3.

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