User:AEE8895/sandbox

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PTEN
Phosphatase and tensin homolog (PTEN) is a tumour suppressor gene whose actions directly affect the activation of primordial follicles. It does this by negatively controlling the PI3K/AKT/mTOR pathway (15). This particular action of PTEN was initially discovered in an experiment using PTEN knockout mice (15). The absence of PTEN within the primordial follicles lead to an increase in AKT phosphorylation. This then creates a subsequent rise in FOXO3 export, as AKT is no longer inhibiting its production (19). This lead to over-activation of the primordial follicles, which resulted in a premature decline of the primordial follicle pool (15).

Foxo3
When Foxo3 is KO in mice models a huge uncontrolled activation of follicles is seen thus the mouse ovaries are deficient of the entire pool of primordial follicles because they have been prematurely activated (ref15). This action is regulated by phosphorylation, the unphosphorylated form is transcriptionally active in the nucleus. However, when phosphorylation occurs the protein is transported to the cytoplasm and loses its transcriptional activity. Pelosi et al noted that the timing and level of the Foxo3 expression is very important to regulate ovarian follicle activation (20).

AKt- PTEN-AKt and Foxo3 are all involved in the same pathway. PTEN is situated upstream of AKt. Therefore, if PTEN is deleted specifically from an oocyte this causes an increase in AKt activity resulting in large numbers of dormant ovarian follicles resuming their growth and differentiation. The TSC complex also plays an important role in this pathways by suppressing the activity of mTOR which has been proven to be essential for maintaining dormancy (22).

TSC and mTOR
Tuberin/tuberous sclerosis complex is also thought to be important in the regulation of primordial follicle activation. TSC negatively controls the function of mTOR (mammalian target of rapamycin). TSC knockout mice have a raised level of mTORC1 activity (17). Suppressing mTORC1 is a necessary process to prevent primordial follicles from being prematurely activated and therefore premature ovarian insufficiency (12).

AMH
AMH (Anti-mullerian Hormone) is a member of the transforming growth factor beta (TGF-b), that has a very important role in regulating both testicular and ovarian function. In the first instance AMH inhibits the initial enrollment of the resting primordial follicles. Secondly AMH prevents the regulation of preantral/small antral follicle growth by reducing their responsiveness to FSH (21).

Cyclin-dependent kinase (Cdk) inhibitor p27
P27 inhibits cell cycle progression at the G1 phase (18) by preventing the action of cyclin E-Cdk2 (19). Due to its’ important role in the cell cycle, it is found within the nucleus of mice oocytes in primordial and primary follicles. During puberty of p27 knock out mice, all primordial follicles are activated and leads to POF. This indicates that p27 is a vital regulator in maintaining a quiescent state in primordial follicles (17).

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