Identification of Sites of STAT3 Action in the Female Reproductive Tract through Conditional Gene Deletion

Robker, Rebecca L.; Watson, Laura N.; Robertson, Sarah A.; Dunning, Kylie R.; McLaughlin, Eileen A.; Russell, Darryl L.

doi:10.1371/journal.pone.0101182

Cited by 24 publications

(27 citation statements)

References 48 publications

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“…Which other factors are involved in the expression of MCP1 in the POAT following estradiol administration? It is known that STAT3 is both an important transcription factor that controls adipose tissue (Richard & Stephens 2014) and reproductive functions (Robker et al 2014). Also, its interaction with the NFKB inflammatory pathway was documented (Sarkö zi et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

et al. 2016

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The objective of our study was to investigate glycemic, oxidative/antioxidative and inflammatory status in letrozole and estradiol valerate induced polycystic ovarian syndrome (PCOS) models. Sixty adult female Wistar rats were divided into four groups: L (0.2 mg letrozole/0.5 ml carboxymethyl cellulose (CMC), daily for 30 days), the control group C L , EV (one i.m. injection of 5 mg EV/0.5 ml sesame oil) and its corresponding control group C EV . After 30 days, ovarian morphology was assessed through ultrasound, serum free testosterone was determined, and an oral glucose tolerance test was performed. Blood, muscle, liver and periovarian adipose tissue (POAT) were collected for oxidative/antioxidative and inflammatory status evaluation. Free testosterone was increased only in the L group, while fasting glycemia was higher in the EV group. Both L and EV led to a significantly decreased level of muscle malondialehyde (MDA) and liver glutathione peroxidase (GPx) activity, while in POAT, MDA level diminished and GPx activity increased. The only difference between the two protocols was in muscle, where after L administration, GPx activity was significantly lower. Implementation of both protocols resulted in an increased expression of pNFKB in muscle, liver and POAT. The expression of monocyte chemoattractant protein 1 (MCP1) increased in liver and POATafter L administration, while in the EV group, MCP1 and STAT3 decreased in POAT. Our study shows that both protocols are characterized by an inflammatory environment in the usually insulin resistant tissues of human PCOS, without generating oxidative stress. In addition, EV has mild metabolic effects and unexpected interference with MCP1 expression in POAT, which require further investigation.

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Section: Discussionmentioning

confidence: 99%

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

et al. 2016

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“…p-STAT3 is known to translocate to the nucleus and increase proliferation-associated gene expression (Annerén 2008, Hiraoka et al 2016. Accordingly, reduced p-STAT3 can induce infertility (Sun et al 2013, Robker et al 2014. Interestingly, p-STAT3 was not decreased at 8 h after E 2 + P 4 treatment in CD31 −/− mice ( Fig.…”

Section: Discussionmentioning

confidence: 88%

The critical role of uterine CD31 as a post-progesterone signal in early pregnancy

Lee

Kim

2017

Reproduction

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CD31 has been shown to play a role in endothelial cell migration and angiogenesis, which are critical to the formation and function of the endometrium and myometrium in uterine development during early pregnancy. However, the role of CD31 in uterine receptivity during blastocyst implantation is poorly understood. The pregnancy rate in female mice mated with male mice was higher than that observed in female mice mated with male mice. During the receptive phase of implantation, uterine glands were more developed in mice than in mice, and the uterine weights of mice were increased. Leukemia inhibitory factor (LIF) was highly expressed in the mice during implantation and the expression of LIF was up-regulated by estradiol-17β ( ) + progesterone ( ) in ovariectomized mice, compared with mice at 8 h after hormone treatment. -induced protein synthesis was inhibited by in the uterus, but not in the uterus of mice. Also, STAT3, HAND2, LIF, and mTOR signals were enhanced in mice. Stromal DNA replication was highly activated in the uterus of mice, manifested by upregulated cyclin series signaling and PCNA expression after + treatment. Collectively, CD31 inhibits -mediated epithelial proliferation via recruitment and phosphorylation of SHP-2 upon receiving signal in early pregnancy.

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“…50,51 The uterine-specific knockout of a downstream target of Gp130 and the LIFR; that is, a signal transducer and activator of transcription 3 (Stat3) also caused the failure of implantation. 51 The epithelium-specific deletion of Stat3 (Wnt7 Cre/+ ; Stat3 flox/ flox ) also was reported recently to show implantation failure, followed by the downregulation of fibroblast growth factors (FGFs) and a cell-cell adhesion protein, cadherin, 52 whereas a stromalspecific deletion (Amhr2 Cre/+ ; Stat3 flox/flox ) simply showed the phenotype with a decreased number of pups, 53 suggesting that the epithelial LIF signaling pathway is indispensable for implantation via FGF signaling. In humans, it was reported that a slight increase in LIF expression was observed at the endometrium before implantation 54 and some clinical studies demonstrated that the LIF expression around the time point of implantation was higher in fertile women, compared to infertile women.…”

Section: Estrogen-dependent Signalingmentioning

confidence: 97%

“…In addition, Wnt7a Cre and Amhr2 Cre transgenic mice were used for epithelial‐specific and SC‐specific deletion, respectively . The deletion of Wnt7a or Amhr2 itself caused a failure of the reproductive organs, suggesting that the phenotype of knockout mice with infertility might be a secondary effect.…”

Section: Outstanding Issuesmentioning

confidence: 99%

“…70 In addition, Wnt7a Cre and Amhr2 Cre transgenic mice were used for epithelial-specific and SC-specific deletion, respectively. 23,53 The deletion of Wnt7a or Amhr2 itself caused a failure of the reproductive organs, suggesting that the phenotype of knockout mice with infertility might be a secondary effect. Lactoferrin-iCre (Ltf Cre ) transgenic mice were developed for the specific deletion of the gene at the epithelium of adult female mice.…”

Section: Limitations Of Knockout Micementioning

confidence: 99%

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Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

Namiki

Ito

Kashiwazaki

2018

Reprod Medicine & Biology

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BackgroundHuman infertility has become a serious and social issue all over the world, especially in developed countries. Numerous types of assisted reproductive technology have been developed and are widely used to treat infertility. However, pregnancy outcomes require further improvement. It is essential to understand the cross‐talk between the uterus (mother) and the embryo (fetus) in pregnancy, which is a very complicated event.MethodsThe mammalian uterus requires many physiological and morphological changes for pregnancy‐associated events, including implantation, decidualization, placentation, and parturition, to occur. Here is discussed recent advances in the knowledge of the molecular mechanisms underlying these reproductive events — in particular, embryonic implantation and decidualization — based on original and review articles.Main findings (Results)In mice, embryonic implantation and decidualization are regulated by two steroid hormones: estrogen and progesterone. Along with these hormones, cytokines, cell‐cycle regulators, growth factors, and transcription factors have essential roles in implantation and decidualization in mice.ConclusionRecent studies using the gene manipulation of mice have given considerable insight into the molecular mechanisms underlying embryonic implantation and decidualization. However, as most of the findings are based on mice, comparative research using different mammalian species will be useful for a better understanding of the species‐dependent differences that are associated with reproductive events, including embryonic implantation.

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Identification of Sites of STAT3 Action in the Female Reproductive Tract through Conditional Gene Deletion

Cited by 24 publications

References 48 publications

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

The critical role of uterine CD31 as a post-progesterone signal in early pregnancy

Molecular mechanisms of embryonic implantation in mammals: Lessons from the gene manipulation of mice

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