New Insights into the Role of Phosphoinositide 3-Kinase Activity in the Physiology of Immature Oocytes: Lessons from Recent Mouse Model Studies

Abstract

The immature oocytes within primordial follicles are arrested at Prophase I of meiosis and remain dormant until awakened by an increase in intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Oocyte PIP3 level is determined by the balance between the activity of phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homologue (PTEN). When this balance favours PI3K, PIP3 levels elevate and trigger the cascade of PI3K/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR) pathway, leading to activation of primordial follicles. This short review aims to provide new insights into the physiological functions of PI3K and PTEN in immature oocytes by summarising recent findings from murine model studies, including oocyte-specific transgenic mice with constitutively-active mutant PI3K.

Keywords: Follicle activation; follicle loss; glanulosa cell tumour; mouse model; phosphatase and tensin homologue (PTEN); phosphatidylinositol (3,4,5)-trisphosphate (PIP3); phosphoinositide 3-kinase (PI3K) pathway.

Figure 1. Diagram of the phosphoinositide 3-kinase pathway in oocyte physiology

Molecules coloured green and purple are negative and positive regulators of the PI3K/AKT/mTORC1 pathway respectively. Red and green lines indicate activation and inhibition of the PI3K/AKT/mTORC1 pathway respectively.^–·^–,–, AKT: protein kinase B; CDKN1B: cyclin-dependent kinase inhibitor 1B; EIF4E: eukaryotic translation initiation factor 4E; EIF4EB1: eukaryotic translation initiation factor 4E binding protein 1; FOXO3: forkhead box 03; JAK: janus kinase; KITL1: KIT ligand 1; MAPK: mitogen-activated protein kinase; MLST8: mTOR associated protein, LST8 homologue; mTOR: mechanistic target of rapamycin; mTORC1: mechanistic target of rapamycin; p: phosphate group; PDK1: phosphoinositide-dependent kinase-1; PI3K: phosphoinositide 3-kinase; PLCγ: phospholipase C, gamma; PTEN: phosphatase and tensin homologue; PRAS40: proline-rich AKT1 substrate of 40 kDa; RHEB: Ras homologue enriched in brain; RPS6: ribosomal protein S6; RPS6KB: ribosomal protein S6 kinase B1; RPTOR: regulatory-associated protein of mTOR; STAT: signal transducer and activator of transcription; TSC: tuberous sclerosis.

Figure 2. Oocyte phosphoinositide 3-kinase activity level and primordial follicle fate

GC: granulosa cell; PI3K: phosphoinositide 3-kinase; PIK3CA*: constitutively active mutant PI3K; PTEN: phosphatase and tensin homologue.