Forkhead transcription factors in ovarian function

Uhlenhaut, N. Henriette; Treier, Mathias

doi:10.1530/rep-11-0092

Cited by 84 publications

(55 citation statements)

References 52 publications

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“…Ovarian follicles develop from primordial follicles to primary follicles, secondary follicles and antral follicles, which become a mature follicle with a single oocyte enclosed by several layers of somatic granulose cells (10). A substantial process is involved in the regulation of follicular development.…”

Section: Discussionmentioning

confidence: 99%

“…Upon binding to the pleckstrin homology domains in the N-terminus in the cell membrane with PIP3, Akt is phosphorylated and activated by the catalysis of 3-phosphoinositide-dependent kinases (48). Activation of Akt, in turn, activates downstream signaling molecules, including FoxO family transcription factors, glycogen synthase kinase 3, Bcl-2 family proteins and mammalian target rapamycin, to regulate physiological processes, including cell proliferation, differentiation and apoptosis (10).…”

Section: Discussionmentioning

confidence: 99%

“…As a vital transcription factor, forkhead box O3a (FoxO3a) negatively regulates primordial follicle activation and early follicular development (8,9). Previous investigations have indicated that FoxO3a is highly expressed and localized to the nucleus during the dormancy of primordial follicles, then is phosphorylated and exported to the cytoplasm during follicular activation in mice (10). However, the activity of FoxO3a is suppressed in later-growing follicles, indicating that the downregulation of FoxO3a in oocytes may be a prerequisite for the initiation of oocyte growth during follicular activation (11,12).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The majority of alveolar rhabdomyosarcoma are characterised by a PAX3-FOXO fusion oncoprotein generated by a 2; 13 chromosomal translocation [7]. It is believed that different stages of folliculogenesis, both in oocytes and in somatic granulosa and theca cells, are regulated by FOXC1, FOXL2, and FOXO subfamily members [8]. A report by Missiaglia et al [9] included 171 patients with alveloar rhabdomyosarcoma, including patients with non-metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Description of a Triad of Rare Malignancies in a Single Patient

Fackrell¹,

Yeo²,

Walji³

2015

CRCM

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We describe the case of a patient diagnosed with a rhabdomyosarcoma and two distinctly separate non-epithelial ovarian cancers. Granulosa cell tumour and Sertoli-Leydig tumour are rare tumours accounting for less than 10% of all ovarian malignancies. Rhabdomyosarcoma is also rare and more commonly seen in childhood. We link these tumours to a mutation in the forkhead transcription factor proteins.

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“…Foxo transcription factors, including Foxo3, are major effectors of the PI3K pathway and are downregulated upon increased activity of the PI3K pathway signaling [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Regulation of FOXO3 subcellular localization by Kit ligand in the neonatal mouse ovary

Ezzati

Baker

Saatcioglu

et al. 2015

J Assist Reprod Genet

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Purpose Foxo3 protein is required in the oocyte nucleus for the maintenance of primordial follicles in a dormant state. PI3K/AKT-dependent phosphorylation of Foxo3 leads to its relocalization to the cytoplasm and subsequent follicular activation. However, the nature of the upstream signals controlling Foxo3 activity and subcellular localization remains unknown. We aimed to study the in vitro effects of Kit ligand (stem cell factor) on the subcellular localization of Foxo3 in primordial follicles within the postnatal mouse ovary. Methods This was an in vitro study using explants of intact neonatal mouse ovaries. The study was performed in laboratory animal facility and basic science research laboratory at a University Hospital. The animals used for this study were FVB mice. Neonatal FVB mice ovaries at postnatal day 7 (PD7) were harvested and incubated in culture medium (DMEM) at 37°C and 5 % CO 2 for 60-90 min with (n=3) or without (n=3) Kit ligand at 150 ng/mL (8 nM). Similar experimental conditions were used to establish a dose-response curve for the effects of Kit ligand and assess the effects of imatinib (small molecule inhibitor of the Kit receptor). Immunofluorescence was used to identify the subcellular location of Foxo3 in oocytes. Proportions of cytoplasmic versus nuclear Foxo3 in primordial follicles were determined. Results Kit ligand treatment increased the cytoplasmic localization of Foxo3 from 40 % in the untreated ovaries to 74 % in the treated group (p=0.007 in paired samples and p=0.03 in unpaired samples). Furthermore, this effect was reversible with imatinib (p=0.005). A dose-response curve for Kit ligand treatment showed that maximum effect was seen at 150 ng/mL. Conclusion Kit ligand treatment in vitro increases the proportion of cytoplasmic Foxo3 in primordial follicles at PD7, lending support to the idea that Kit receptor/ligand controls Foxo3 activity in the context of primordial follicle activation

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Forkhead transcription factors in ovarian function

Cited by 84 publications

References 52 publications

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

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

Description of a Triad of Rare Malignancies in a Single Patient

Regulation of FOXO3 subcellular localization by Kit ligand in the neonatal mouse ovary

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