Cre-mediated recombination in cell lineages that express the progesterone receptor

Soyal, Selma M.; Mukherjee, Atish; Lee, Kevin Y.-S.; Li, Jie; Li, Huaiguang; DeMayo, Francesco J.; Lydon, John P.

doi:10.1002/gene.20098

Cited by 338 publications

(422 citation statements)

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“…Because the systemic Rac1 null mice are embryonic lethal owing to gastrulation defects, 24 to analyze the pathophysiological significance of Rac1 in early pregnancy events, we next used a progesterone receptor (Pgr)-driven Cre (Pgr cre/+ ) mouse model crossed with Rac1 floxed (Rac1 f/f ) mice to achieve uterine-selective deletion of Rac1. [25][26][27] As shown in To ascertain the stage-specific causes accounting for this obvious infertility, we subsequently analyzed the implantation status in mice missing uterine Rac1. Although all Rac1 f/f mice tested showed normal embryo implantation on day 5 morning (Figure 2j).…”

Section: Resultsmentioning

confidence: 99%

“…26,27 Uterine-specific mutant mice were generated by crossing Rac1 f/f mice with Pgr Cre/+ mice. 25 All mice were housed in the animal care facility of the Institute of Zoology, Chinese Academy of Sciences, according to the institutional guidelines for the care and use of laboratory animals. Female mice were mated with fertile wild-type males to induce pregnancy (vaginal plug = day 1 of pregnancy).…”

Section: Discussionmentioning

confidence: 99%

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Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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“…To effectively investigate the role of Mig-6 in the regulation of uterine function and the response to hormonal stimulation, we generated a Mig-6 conditional null allele, the Mig-6 flox allele (Mig-6 f/f ) (33). Mig-6 f/f mice were bred to PR Cre (34) mice to generate conditional Mig-6 ablation (PR cre/ϩ Mig-6 f/f ; Mig-6 d/d ) in the reproductive tract. Significant morphological differences in the uteri of Mig-6 d/d and Mig-6 f/f were not observed at 2 months of age.…”

Section: The Epithelial Hyperplastic Effect In Mice With Conditional mentioning

confidence: 99%

“…Mig-6 d/d mice were completely infertile (Table S3). Since the PR Cre mouse shows Cre recombinase activity in the pituitary, ovary, uterus, and mammary gland, the cause of infertility in these mice may be the result of a defect in any of these tissues (34 Thus, to determine if the infertility was in part because of loss of the ability of the uterus to support implantation, we investigated the ability of the uterus to undergo a decidual reaction. Ovariectomized female Mig-6 f/f and Mig-6 d/d mice (n ϭ 3) were treated with hormones and the uterus was mechanically stimulated to mimic the signaling of the embryo at implantation and to induce decidualization.…”

Section: The Epithelial Hyperplastic Effect In Mice With Conditional mentioning

confidence: 99%

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Jeong

Lee

et al. 2009

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

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Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6 d/d mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6 d/d mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.estrogen ͉ endometrial cancer ͉ progesterone ͉ progesterone receptor ͉ SRC-1

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“…These systems fulfill the purpose of generating somatic mutations of a target gene at a given time during the animal's life-span and in a specific cell type. In this respect, there are few studies that have shown Cremediated gene recombination in uterine cells (Jamin et al, 2003;Soyal et al, 2005;Wen et al, 2003). For example, a progesterone receptor Cre (PR-Cre) knockin mouse line has been shown to be able to target various progesterone-responsive tissues including the uterus, ovary, oviduct, pituitary gland, and mammary gland (Soyal et al, 2005).…”

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confidence: 99%

Conditional gene recombination by adenovirus-driven Cre in the mouse uterus

Wang

Xie

Zhang

et al. 2006

genesis

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SummaryCre-mediated conditional gene targeting has been shown to be successful in many cell and tissue types. However, gene recombination in the uterus with heterogeneous cell types by Cre activation is not yet well established. Using recombinant adenoviruses expressing a functional Cre (ADVCre) and ROSA26 reporter mice, we show here that ADV-Cre infused intraluminally in a small volume (10 μl) conditionally excises the loxP site, resulting in lacZ expression in uterine luminal epithelial cells without significantly affecting pregnancy. In contrast, a similar intraluminal infusion of ADV-Cre in a larger volume (50 μl) damages the normal architecture and integrity of the luminal epithelium, inducing gene recombination in the underneath stromal cells, with disruption of pregnancy. Further, decidualizing stromal cells at the implantation sites can be targeted by ADV-Cre after intravenous administration on days 5-6. This route of administration also elicits Cre activity in other tissues, including the liver, spleen, ovary, and, more remarkably, in the adrenal cortex. These findings demonstrate the feasibility of achieving conditional expression or deletion of specific genes in uterine cells at desired times and physiological states.

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Cre-mediated recombination in cell lineages that express the progesterone receptor

Cited by 338 publications

References 17 publications

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Conditional gene recombination by adenovirus-driven Cre in the mouse uterus

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