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Figure 1: Pathways in primordial follicle activation (adapted from[5],[20]). (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.[65] PI3K complex convert PIP2 to PIP3 which is the key element of PI3K pathway and activate the nuclear translocation and phosphorylate AKT (p-AKT).[66],[67] p-AKT enhances primordial follicle activation by inhibition of the phosphorylation of FOXO3a[68] as the deletion of FOXO3a initiated the activation of primordial follicle in mouse model.[69],[70] 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.[71],[72] PTEN is the regulator to convert PIP3 to PIP2 and which keep the primordial follicle as dormant.[73],[74] PDK1 is a master kinase, which is another regulator for the activation of AKT/PKB and many other AGC kinases.[75] PI3K-mediated signaling partially converges at PDK1. PDK1 activates AKT via phosphorylating AKT at T308.[68] (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.[5] 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.[20] 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.

Figure 1: Pathways in primordial follicle activation (adapted from<sup>[5],[20]</sup>). (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.<sup>[65]</sup> PI3K complex convert PIP2 to PIP3 which is the key element of PI3K pathway and activate the nuclear translocation and phosphorylate AKT (p-AKT).<sup>[66],[67]</sup> p-AKT enhances primordial follicle activation by inhibition of the phosphorylation of FOXO3a<sup>[68]</sup> as the deletion of FOXO3a initiated the activation of primordial follicle in mouse model.<sup>[69],[70]</sup> 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.<sup>[71],[72]</sup> PTEN is the regulator to convert PIP3 to PIP2 and which keep the primordial follicle as dormant.<sup>[73],[74]</sup> PDK1 is a master kinase, which is another regulator for the activation of AKT/PKB and many other AGC kinases.<sup>[75]</sup> PI3K-mediated signaling partially converges at PDK1. PDK1 activates AKT via phosphorylating AKT at T308.<sup>[68]</sup> (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.<sup>[5]</sup> 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.<sup>[20]</sup> 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.