Maternal phosphatidylinositol 3-kinase signalling is crucial for embryonic genome activation and preimplantation embryogenesis. Zheng W et al. Maternal effect factors derived from oocytes are important for sustaining early embryonic development before the major wave of embryonic genome activation (EGA). In this study, we report a two-cell-stage arrest of embryos lacking maternal 3-phosphoinositide-dependent protein kinase 1 as a result of suppressed EGA. Concurrent deletion of maternal Pten completely rescued the suppressed EGA and embryonic progression through restored AKT signalling, which fully restored the fertility of double-mutant females. Our study identifies maternal phosphatidylinositol 3-kinase signalling as a new maternal effect factor that regulates EGA and preimplantation embryogenesis in mice.
Expression regulated by
Comment
Ovarian localization
Oocyte, Ovarian tumor
Comment
Insulin Signaling in Mammalian Oocytes. Acevedo N et al. Continual exposure of follicles/oocytes to elevated insulin compromises embryonic developmental competence, yet cellular mechanisms are unknown. Objectives of present studies were to determine if mouse oocytes have insulin receptors, a functional insulin signaling cascade, and whether insulin exposure during oocyte growth or maturation influences meiotic progression and chromatin remodeling. Immunoblot and immunocytochemical analyses of germinal vesicle-intact (GVI) oocytes demonstrated presence of insulin receptor-beta. Insulin receptor expression was increased in oocytes following gonadotropin stimulation, and remained elevated throughout meiotic maturation. Fully-grown GVI oocytes contained 3-phosphoinositide dependent protein kinase-1 (PDPK1), thymoma viral proto-oncogene 1 (AKT1) and glycogen synthase kinase 3 (GSK3). In vitro maturation of GVI oocytes in 5 microg/ml insulin had no influence on meiotic progression or incidence of normal MII chromosome condensation. Treatment of oocytes during maturation had no effect on GSK3A/B protein expression or phosphorylation on S21/9. However, culture of pre-antral follicles for 10 days with 5 microg/ml insulin increased phosphorylation of oocyte GSK3B, indicating GSK3 inactivation. Rate of development to MI was similar between oocytes obtained from insulin treated follicles and controls, yet incidence of abnormal MI chromatin condensation was significantly higher in oocytes obtained from follicles cultured with insulin compared to no insulin. These results demonstrate that oocytes contain a functional insulin signaling pathway and that insulin exposure during oocyte growth results in chromatin remodeling aberrations. These findings begin to elucidate mechanisms by which chronic elevated insulin influences oocyte meiosis, chromatin remodeling, and embryonic developmental competence.
Follicle stages
Comment
An immunohistochemical perspective of PPARbeta and one of its putative targets PDK1 in normal ovaries, benign and malignant ovarian tumours. Ahmed N et al. Peroxisome proliferator-activated receptor beta (PPARbeta) is a member of the nuclear hormone receptor family and is a ligand-activated transcription factor with few known molecular targets including 3-phosphoinositide-dependent protein kinase 1(PDK1). In view of the association of PPARbeta and PDK1 with cancer, we have examined the expression of PPARbeta and PDK1 in normal ovaries and different histological grades of ovarian tumours. Normal ovaries, benign, borderline, grades 1, 2 and 3 ovarian tumours of serous, muciuous, endometrioid, clear cell and mixed subtypes were analysed by immunohistochemistry for PPARbeta and PDK1 expression. All normal ovarian tissues, benign, borderline and grade 1 tumours showed PPARbeta staining localised in the epithelium and stroma. Staining was predominantly nuclear, but some degree of cytoplasmic staining was also evident. Approximately 20% of grades 2 and 3 tumours lacked PPARbeta staining, whereas the rest displayed some degree of nuclear and cytoplasmic staining of the scattered epithelium and stroma. The extent of epithelial and stromal PPARbeta staining was significantly different among the normal and the histological grades of tumours (chi(2)=59.25, d.f.=25, P<0.001; chi(2)=64.48, d.f.=25, P<0.001). Significantly different staining of PPARbeta was observed in the epithelium and stroma of benign and borderline tumours compared with grades 1, 2 and 3 tumours (chi(2)=11.28, d.f.=4, P<0.05; chi(2)=16.15, d.f.=4, P<0.005). In contrast, PDK1 immunostaining was absent in 9 out of 10 normal ovaries. Weak staining for PDK1 was observed in one normal ovary and 40% of benign ovarian tumours. All borderline and malignant ovarian tumours showed positive cytoplasmic and membrane PDK1 staining. Staining of PDK1 was confined to the epithelium and the blood vessels, and no apparent staining of the stroma was evident. Significantly different PDK1 staining was observed between the benign/borderline and malignant ovarian tumours (chi(2)=22.45, d.f.=5, P<0.001). In some borderline and high-grade tumours, staining of the reactive stroma was also evident. Our results suggest that unlike the colon, the endometrial, head and neck carcinomas, overexpression of PPARbeta does not occur in ovarian tumours. However, overexpression of PDK1 was evident in borderline and low- to high-grade ovarian tumours and is consistent with its known role in tumorigenesis.British Journal of Cancer advance online publication, 18 March 2008; doi:10.1038/sj.bjc.6604306 www.bjcancer.com.
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Reddy P et al. The molecular mechanisms that control reproductive aging and menopausal age in females are poorly understood. Here, we provide genetic evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) signaling in oocytes preserves reproductive lifespan by maintaining the survival of ovarian primordial follicles. In mice lacking the PDK1-encoding gene Pdk1 in oocytes, the majority of primordial follicles are depleted around the onset of sexual maturity, causing premature ovarian failure (POF) during early adulthood. We further showed that suppressed PDK1-Akt-p70 S6 kinase 1 (S6K1)-ribosomal protein S6 (rpS6) signaling in oocytes appears to be responsible for the loss of primordial follicles, and mice lacking the Rps6 gene in oocytes show POF similar to that in Pdk1-deficient mice. In combination with our earlier finding that phosphatase and tensin homolog deleted on chromosome ten (PTEN) in oocytes suppresses follicular activation, we have now pinpointed the molecular network involving phosphatidylinositol 3 kinase (PI3K)/PTEN-PDK1 signaling in oocytes that controls the survival, loss, and activation of primordial follicles, which together determine reproductive aging and the length of reproductive life in females. Underactivation or overactivation of this signaling pathway in oocytes is shown to cause pathological conditions in the ovary, including POF and infertility.
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Deficiency of Pdk1 contributes to primordial follicle activation via the upregulation of YAP expression and the pro‑inflammatory response. Gao J et al. (2020) The molecular mechanisms underlying the activation of primordial follicles are poorly understood. The serine/threonine protein kinase phosphoinositide‑dependent kinase 1 (PDK1), a pivotal downstream effector of phosphatidyl inositol‑3 kinase (PI3K) signaling, plays a vital role in cellular signaling. In order to identify the function of PDK1 in ovarian follicle development, this study used conditional Pdk1 deletion in mouse oocytes by crossing Pdk1loxP/loxP mice with transgenic mice carrying Gdf‑9 promoter‑mediated Cre recombinase and found that Pdk1flx/flxGdf9Cre mice were subfertile with increased serum follicle‑stimulating hormone (FSH) and luteinizing hormone (LH) levels compared with Pdk1flx/flx mice. The deletion of Pdk1 in oocytes induced massive primordial follicle activation, leading to premature ovarian failure (POF). Further investigation revealed that enhanced Yes‑associated protein (YAP) expression and an increased pro‑inflammatory response also contributed to massive primordial follicle activation. PDK1 formed the complex with the core kinases of Hippo signaling and regulated the expression levels of YAP. On the whole, the findings of the present study demonstrate that PDK1 serves as an indispensable gatekeeper for maintaining the primordial follicle pool and provide a deeper understanding of POF treatment.//////////////////