Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice

Lan, Zi-Jian; Krause, M.S.; Redding, S.D.; Li, X.; Wu, Gang; Zhou, Huaxin; Bohler, Henry; Ko, CheMyong; Cooney, Austin J.; Zhou, Junmei; Lei, Zhenmin

doi:10.1016/j.mce.2017.01.043

Cited by 27 publications

(22 citation statements)

References 61 publications

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“…Therefore, to verify the involvement of the PI3K in the regulation of ovine primordial follicle activation in vitro, we tested the hypothesis that pharmacological inhibition of the PI3K pathway with LY294002 would inhibit the initiation of follicle growth. LY294002 has been used at different concentrations (from 1 μM to 50 μM) and incubation periods (from 20 min to 14 days) to inhibit the PI3K pathway in different ovarian cells (Reddy et al, 2009;Mani et al, 2010;Adhikari et al, 2013;Zhang et al, 2014;Fujihara et al, 2014;Lan et al, 2017). In this study, although the concentration of the inhibitor (50 µM LY294002) is higher than most of the other studies (Keating et al, 2009;Sobinoff et al, 2012;Zhang et al, 2014;Zhao et al, 2017), our findings support the idea that this concentration was not toxic because it did not reduce the percentage of normal follicles compared to the treatment without the inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Blocking the PI3K pathway or the presence of high concentrations of EGF inhibits the spontaneous activation of ovine primordial follicles in vitro

Santos¹,

Santos²,

Menezes³

et al. 2017

Anim Reprod

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The aims of this study were to verify the effects of Epidermal Growth Factor (EGF) on the morphology, primordial follicle activation, growth and proliferation of granulosa cells of ovine follicles cultured in situ, as well as the effect of a PI3K inhibitor on the follicular activation. Ten ovine ovaries were divided into fragments, being one fixed for histological analysis (fresh control). The remaining fragments were cultured for 7 days in control medium (α-MEM + ) alone or supplemented with EGF (1, 10, 50, 100 or 200 ng/mL). Follicles were classified as normal or atretic, as primordial or growing, and the oocyte and follicle diameters were measured. PCNA immunohistochemistry was performed in the fresh control and in treatment that showed the best results for follicular activation. Pharmacologic inhibition of PI3K activity was performed through pretreatment in media added with 50 µM LY294002 for 1 h. The percentage of normal follicles decreased (P < 0.05) after 7 days of culture in all treatments compared to the fresh control. A significant reduction in the percentage of primordial follicles and an increase (P < 0.05) in the growing ones were observed in all treatments compared to fresh control. Furthermore, both the control medium and 1 ng/mL EGF promoted an increase (P < 0.05) in follicular activation compared to other EGF treatments. The PCNA-positive cells in the EGF treatment were higher (P < 0.05) than in fresh control and α-MEM + . Pretreatment of ovarian tissue with PI3K inhibitor significantly inhibited (P < 0.05) α-MEM + -stimulated primordial follicle activation, but had no effect on EGF-stimulated activation (P > 0.05). In conclusion, PI3K pathway mediates the in vitro spontaneous activation of sheep primordial follicles. Moreover, EGF may act indirectly on follicular activation by promoting granulosa cell proliferation at 1 ng/mL, and EGF inhibited follicle activation in concentrations similar or higher than 10 ng/mL.

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Section: Discussionmentioning

confidence: 99%

Blocking the PI3K pathway or the presence of high concentrations of EGF inhibits the spontaneous activation of ovine primordial follicles in vitro

Santos¹,

Santos²,

Menezes³

et al. 2017

Anim Reprod

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“…However, it has also been reported that human ovarian follicles in culture treated with bpV(pic) or bpV(HOpic) displayed limited growth and reduced survival [ 126 , 202 ]. In addition, deletion of PTEN in ovarian theca cells resulted in aberrant androgenesis and early fertility loss, reminiscent of human polycystic ovary syndrome [ 203 ]. Thus, transient low-dose inhibition of PTEN during in vitro manipulation of ovarian cells arises as a suitable approach to improve in vitro fertilization techniques.…”

Section: Pten Inhibition By Small Molecules In Human Disease Theramentioning

confidence: 99%

PTEN Inhibition in Human Disease Therapy

Pulido

2018

Molecules

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The tumor suppressor PTEN is a major homeostatic regulator, by virtue of its lipid phosphatase activity against phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], which downregulates the PI3K/AKT/mTOR prosurvival signaling, as well as by its protein phosphatase activity towards specific protein targets. PTEN catalytic activity is crucial to control cell growth under physiologic and pathologic situations, and it impacts not only in preventing tumor cell survival and proliferation, but also in restraining several cellular regeneration processes, such as those associated with nerve injury recovery, cardiac ischemia, or wound healing. In these conditions, inhibition of PTEN catalysis is being explored as a potentially beneficial therapeutic intervention. Here, an overview of human diseases and conditions in which PTEN inhibition could be beneficial is presented, together with an update on the current status of specific small molecule inhibitors of PTEN enzymatic activity, their use in experimental models, and their limitations as research or therapeutic drugs.

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“…Animal genotyping was performed by PCR, as described previously, with genomic DNA isolated from tail clips of mice. 18 The PCR primers are listed in Table 1. For a fertility test, six 2-montheold Ggnbp2-null and WT male mice were mated with proven fertile females (one male/one female per cage) for 6 months.…”

Section: Animalsmentioning

confidence: 99%

“…The number of pups produced from each female was recorded, as described previously. 18 All of the mice were raised under standard laboratory conditions, with a 12-hour light/ dark cycle and free access to food and water. Mice were euthanized under ketamine anesthesia for tissue and blood collections, and efforts were made to minimize their discomfort.…”

Section: Animalsmentioning

confidence: 99%

Ggnbp2-Null Mutation in Mice Leads to Male Infertility due to a Defect at the Spermiogenesis Stage

Liu

Guo

et al. 2017

The American Journal of Pathology

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Gametogenetin binding protein 2 (GGNBP2) is an evolutionarily conserved zinc finger protein. Although Ggnbp2-null embryos in the B6 background died because of a defective placenta, 6.8% of Ggnbp2-null mice in the B6/129 mixed background were viable and continued to adulthood. Adult Ggnbp2-null males were sterile, with smaller testes and an azoospermic phenotype, whereas mutant females were fertile. Histopathological analysis of 2-month-old Ggnbp2-null testes revealed absence of mature spermatozoa in the seminiferous tubules and epididymides and reduction of the number of spermatids. Ultrastructural analysis indicated dramatic morphological defects of developing spermatids in the Ggnbp2-null testes, including irregularly shaped acrosomes, acrosome detachment, cytoplasmic remnant, ectopic manchette, and ill-formed head shape in both elongating and elongated spermatids. However, the numbers of spermatogonia, spermatocytes, Leydig cells, and Sertoli cells in Ggnbp2-null testes did not significantly differ from the wild-type siblings. Gonadotropins, testosterone, and the blood-testis barrier were essentially unaffected. Western blot analyses showed increases in α-E-catenin, β-catenin, and N-cadherin, decreases in E-cadherin, afadin, and nectin-3, and no changes in vinculin, nectin-2, focal adhesion kinase, and integrin-β1 protein levels in Ggnbp2-null testes compared to wild-type siblings. Together, this study demonstrates that GGNBP2 is critically required for maintenance of the adhesion integrity of the adlumenal germ epithelium and is indispensable for normal spermatid transformation into mature spermatozoa in mice.

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Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice

Cited by 27 publications

References 61 publications

Blocking the PI3K pathway or the presence of high concentrations of EGF inhibits the spontaneous activation of ovine primordial follicles in vitro

Blocking the PI3K pathway or the presence of high concentrations of EGF inhibits the spontaneous activation of ovine primordial follicles in vitro

PTEN Inhibition in Human Disease Therapy

Ggnbp2-Null Mutation in Mice Leads to Male Infertility due to a Defect at the Spermiogenesis Stage

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