Oocyte-Specific Deletion of
            <i>Pten</i>
            Causes Premature Activation of the Primordial Follicle Pool

Reddy, Pradeep; Liu, Lian; Adhikari, Deepak; Jagarlamudi, Krishna; Singareddy, Rajareddy; Shen, Yan; Du, Chun; Tang, Wenli; Hämäläinen, Tuula; Peng, Stanford L.; Lan, Zi-Jian; Cooney, Austin J.; Huhtaniemi, Ilpo; Liu, Kui

doi:10.1126/science.1152257

Cited by 734 publications

(641 citation statements)

References 10 publications

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“…No malignancy was found in mouse or human ovarian grafts or hosts during prolonged transplantation, indicating the present shortterm exposure to the PTEN inhibitor had minimal adverse effects despite the known function of PTEN as a tumor suppressor gene (29). These findings are consistent with a lack of tumorigenesis in mutant mice with PTEN deletion in oocyte or granulosa cells (3,30).…”

Section: Discussionsupporting

confidence: 77%

See 1 more Smart Citation

Activation of dormant ovarian follicles to generate mature eggs

Kawamura

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

379

340

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Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.

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Section: Discussionsupporting

confidence: 77%

“…Studies using mutant mice indicated that oocyte-specific deletion of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) gene promotes the growth of all primordial follicles in neonatal and adult animals (3)(4)(5). The PTEN gene encodes a phosphatase enzyme that negatively regulates the PI3K-Akt signaling pathway.…”

mentioning

confidence: 99%

Activation of dormant ovarian follicles to generate mature eggs

Kawamura

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

379

340

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“…FoxO3a -/-mice exhibited global activation of primordial follicles and age-dependent infertility (8,40). Oocyte-specific ablation of phosphatase and tensin homolog (a negative regulator of PI3Ks) led to PI3K-induced Akt activation, and thus, phosphorylated FoxO3a, suppressing its activity, and consequently triggering a phenotype in oocytes equivalent to that in mice lacking FoxO3a (41,42). The reduced phosphorylation of FoxO3a observed in the present study would maintain FoxO3a localization in the nuclei, which prevents the activation of follicle development.…”

Section: Discussionmentioning

confidence: 99%

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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“…For example, it was reported that PTEN is required for the maintenance of hematopoietic stem cell populations while inhibiting blood cancer stem cells, suggesting that the enhancing/restoring PTEN function might be a promising therapeutic approach to combat blood cancer stem cells without eliminating normal blood stem cells (Yilmaz et al, 2006;Zhang et al, 2006). Additionally, PTEN was shown to control ovarian follicle activation and therefore reproduction of mammals (Reddy et al, 2008). The roles of PTEN in the development and function of specific organs/tissues, such as brain, heart, and bone, have also been reported (Backman et al, 2001;Groszer et al, 2001;Kwon et al, 2001Kwon et al, , 2006Crackower et al, 2002;Liu et al, 2007;Oudit et al, 2008).…”

Section: Pten As a Multifunctional Biological Regulatormentioning

confidence: 99%

Post-translational regulation of PTEN

Wang

Jiang

2008

Oncogene

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PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor regulates a variety of cellular processes including cell proliferation, growth, migration and death. This master regulator itself is also under deliberative regulation. Although the evidence for PTEN regulation and its significance in normal biology and disease is overwhelming, the mechanisms and exact functional consequences of PTEN regulation are far from clear. In this review, we discuss recent advances concerning post-translational regulation of PTEN in general, and in more detail about its regulation by ubiquitination. We also discuss some unsolved questions in the field and how they might be addressed in the future. We propose that the complex regulatory mechanisms of PTEN dictate how this tumor suppressor executes its distinct biological functions.

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Oocyte-Specific Deletion of Pten Causes Premature Activation of the Primordial Follicle Pool

Cited by 734 publications

References 10 publications

Activation of dormant ovarian follicles to generate mature eggs

Activation of dormant ovarian follicles to generate mature eggs

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

Post-translational regulation of PTEN

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