Figure 1: Pathways in primordial follicle activation (adapted from,). (a) PI3K-PTEN-AKT-FOXO3-mTOR pathway in primordial follicle activation. The initiating factors of this process are largely unknown. Upgraded Kit legand from GCs of primordial follicle binds to its KIT/tyrosine kinase receptor, KIT on the surface of oocyte and activate the PI3K complex. PI3K complex convert PIP2 to PIP3 which is the key element of PI3K pathway and activate the nuclear translocation and phosphorylate AKT (p-AKT)., p-AKT enhances primordial follicle activation by inhibition of the phosphorylation of FOXO3a as the deletion of FOXO3a initiated the activation of primordial follicle in mouse model., p-AKT activates mTOR complex 1 (mTORC1) by inhibiting tuberous sclerosis complex 1/2 (TSC1/2, or tuberin). mTORC1 then phosphorylates S6K which activates S6 to phosphorylates S6 as a sequence. Also, mTORC1 inhibits the phosphorylation of 4EBP1, which functions together with p-S6 are highly involved in cell growth and proliferation., PTEN is the regulator to convert PIP3 to PIP2 and which keep the primordial follicle as dormant., PDK1 is a master kinase, which is another regulator for the activation of AKT/PKB and many other AGC kinases. PI3K-mediated signaling partially converges at PDK1. PDK1 activates AKT via phosphorylating AKT at T308. (b) The Hippo signaling pathway in primordial follicle activation. Ovarian tissue fragmentation transforms G-Actin to F-Actin by inducing the actin polymerization which disrupts the Hippo signaling pathway by decreasing the expression of MST1/2 and SAV1 complex. It then phosphorylates LATS1/2 which inhibit the phosphorylation YAP and TAZ, two major downstream effectors of the Hippo pathway. Dephosphorylated YAP/TAZ translocate into the nucleus and interact with the transcription factors such as TEAD1-4 then stimulate the expression of downstream CCN growth factors and BIRC apoptosis inhibitors, leading to initiates primordial follicle activation and development. PI3K: Phosphatidylinositol-3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; GC: Granuloca cells; KIT: KIT Proto-Oncogene Receptor Tyrosine Kinase; mTORC1: Target of Rapamycin complex 1; 4EBP1: 4E-Binding Protein 1; PIP3: Phosphatidylinositol 3,4,5 trisphosphate; PIP2: Phosphatidylinositol (4,5)-bisphosphate; PDK1: 3-Phosphoinositide-dependent protein kinase-1; PKB: Protein kinase B; F-actin: Filamentous actin; G-actin: Globular actin; MST1/2: Mammalian sterile 20 -like kinase-1/2; homologs of Drosophila Hippo; SAV1: Homolog of Drosophila Salvador; LATS1/2: Mammalian homologs of Drosophila Warts; YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZbinding motif; TEAD transcriptional factors: Transcription factors containing the TEA/ATTS DNA binding domain; CCN growth factors – Acronym derived from three of its members: CCN1 (cysteine-rich angiogenic protein 61), CCN2 (connective tissue growth factor), and CCN3 (nephroblastoma overexpressed); BIRC apoptosis inhibitors: Baculoviral inhibitors of apoptosis repeat-containing proteins.