Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary

Zheng, Wenjing; Gorre, Nagaraju; Liu, Zhilin; Liu, Kui

doi:10.1016/j.mce.2011.05.027

Cited by 152 publications

(116 citation statements)

References 68 publications

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“…PI3K is one of the most relevant proteins that controls steroidogenesis (Moore et al, 2001;Shimada et al, 2003;Yu et al, 2005;Su et al, 2006;Ebeling et al, 2011) and has defined actions in the activation and survival of primordial follicles, and in the recruitment of follicles (Zheng et al, 2012). PI3K controls steroidogenesis, an effect that has been observed by using 100 μM of its inhibitor, LY294002, a dose used by Hoshino et al (2004).…”

Section: Discussionmentioning

confidence: 99%

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Effects of PI3K and FSH on steroidogenesis, viability and embryo development of the cumulus–oocyte complex after in vitro culture

Souza

Salles

Camargo

et al. 2017

Zygote

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SummaryThe purpose of this study was to evaluate the effects of FSH and PI3K on the nuclear maturation, viability, steroidogenesis and embryo development of bovine cumulus-oocyte complexes (COCs). Oocyte maturation was achieved with MIV B, MIV B+100 µM LY294002, MIV B+10 ng/mL follicle stimulating hormone (FSH), or MIV B+10 ng/mL FSH+100 µM LY294002 treatments for 22-24 h. After the cultured COCs were denuded, oocytes were separated into those that extruded polar bodies (mature) and those that did not, and real-time polymerase chain reaction (PCR) for BAX, BCL2, LHR, FSHR, CYP11A1, CYP19A1 and HSD17B1 genes was performed. The culture medium was collected to determine the levels of 17β-estradiol (E2) and progesterone (P4). The trypan blue test was used to study COC viability, and embryo development was evaluated. FSH increased nuclear maturation and PI3K blocked the maturation but did not influence oocyte viability. BAX and BCL2 expression levels in the cumulus cells were only affected by FSH, and the BAX levels decreased after treatment with LY294002. FSH increased the levels of E2 and P4, however inhibition of PI3K decreased E2 levels. MIV B enhanced levels of LHR, FSHR, CYP11A1, CYP19A1 and HSD17B1, whereas LY294002 inhibited the expression levels of all genes. MIV B+FSH decreased the expression levels of all genes except CYP11A1. LY294002 did not demonstrate any effects in the presence of FSH. Embryo development was significantly decreased when the MIV B+FSH medium was used. In conclusion, FSH controls the steroidogenesis, viability and gene expression in COCs. PI3K plays essential roles in nuclear maturation, steroidogenesis and embryo development.

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Section: Discussionmentioning

confidence: 99%

“…The catalytic subunit can be p110α, p110β, p110γ or p110δ and promotes the activation of complex intracellular signalling using proteins including AKT/PKB, FOXO, PDK1, mTOR, MAPK and others (Engelman et al, 2006;Vanhaesebroeck et al, 2010;Zheng et al, 2012).…”

Section: Effects Of Pi3k and Fsh On Steroidogenesis Viability And Emmentioning

confidence: 99%

Effects of PI3K and FSH on steroidogenesis, viability and embryo development of the cumulus–oocyte complex after in vitro culture

Souza

Salles

Camargo

et al. 2017

Zygote

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“…First, we incubated the GOCs in the presence of LY294002, a chemical inhibitor of the phosphatidylinositol-3-kinase (PI3K) signaling pathway whose activity has been implicated in oocyte growth (Zheng et al 2012). After 7 days of culture, the granulosa cells were removed and the diameter and mtDNA content of oocytes were determined.…”

Section: Accumulation Of Mtdna Is Mechanistically Uncoupled From Oocymentioning

confidence: 99%

Regulation of mitochondrial DNA accumulation during oocyte growth and meiotic maturation in the mouse

Mahrous¹,

Yang²,

Clarke³

2012

Reproduction

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Oocytes accumulate an enormous quantity of mitochondrial (mt) DNA, and an insufficient amount of mtDNA may underlie some cases of poor oocyte quality leading to infertility. Little is known, however, about the mechanisms that govern the timing and regulation of mtDNA accumulation during oogenesis. We report, through analysis of the mtDNA content of individual oocytes of the mouse, that mtDNA accumulates steadily during oocyte growth to reach a value of w175 000 copies per cell. MtDNA content ceases to increase once oocytes reach full size and remains unchanged during meiotic maturation. To test whether mtDNA accumulation depends on oocyte growth, we inhibited growth in vitro in two ways -by exposing complexes comprising partially grown oocytes enclosed by granulosa cells to a chemical inhibitor of the phosphatidylinositol-3-kinase signaling pathway and by removing the surrounding granulosa cells from partially grown oocytes. Under both conditions, the oocytes fail to grow, but mtDNA accumulation is unaffected, indicating that the two processes can be mechanistically uncoupled. Quantitative analysis of the mRNAs encoding proteins required for mtDNA replication revealed that Polg (Polga) (polymerase-g, a-subunit), Polg2 (Polgb), and Tfam (transcription factor A, mitochondrial) increase during oocyte growth but then decrease after fully grown oocytes become transcriptionally silent as indicated by the non-surrounded nucleolusto-surrounded nucleolus transition. Thus, there is a correlation between the decline in the quantity of mRNAs encoding mtDNA replication factors in fully grown oocytes and the arrest of mtDNA accumulation in these cells, suggesting that the two events may be causally linked.

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“…John et al (12) reported that as the downstream of PI3K/Akt, hyperphosphorylation of FoxO3a induced over-activation of primordial follicules (8,26,28). As previous studies have systematically reported that maintaining optimal activities of PI3K/Akt signaling pathway is essential for normal ovarian function, which not only regulates the balance between survival and activation of primordial follicles, but also is vital for the proliferation and differentiation of GCs (26)(27)(28). These studies suggested that regulation of the optimal expression level of FoxO3a is important spatially and temporally during follicular development.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have systematically reported that maintaining optimal activity of Akt serine/threonine kinase 1 (Akt) signaling is essential for normal ovarian function, which regulates the balance between survival and activation of primordial follicles, and also is important for proliferation and differentiation of GCs (26)(27)(28). FoxO3a is also a substrate of Akt, thus, the present study also examined the expression of Akt ovaries.…”

Section: Introductionmentioning

confidence: 95%

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Zhang

Liao

et al. 2016

Molecular Medicine Reports

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Abstract. Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity-induced infertility is not yet clear. The present study established a high-fat diet (HFD)-induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD-induced obesity on follicular development in the mouse ovary. The 4-week-old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time-dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD-induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time-dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.

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Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary

Cited by 152 publications

References 68 publications

Effects of PI3K and FSH on steroidogenesis, viability and embryo development of the cumulus–oocyte complex after in vitro culture

Effects of PI3K and FSH on steroidogenesis, viability and embryo development of the cumulus–oocyte complex after in vitro culture

Regulation of mitochondrial DNA accumulation during oocyte growth and meiotic maturation in the mouse

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

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