Apoptosis at the time of embryo implantation in mouse and rat

Pampfer, S.; Donnay, Isabelle

doi:10.1038/sj.cdd.4400516

Cited by 121 publications

(75 citation statements)

References 137 publications

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“…It has been proposed that TNFα may have an essential role in uterine epithelial cell apoptosis. 38 Thus, we wondered whether Rac1 could mediate this process. We then analyzed the expression of TNFα and its related receptor TNFRI on day 5 of pregnancy.…”

Section: Resultsmentioning

confidence: 99%

“…TNFα has been demonstrated to be essential for epithelial cell apoptosis and it could upregulate the level of Rac1-GTP in intestinal epithelial cells. 38,59 P38 signaling is also important for luminal epithelial cell apoptosis and P38 is a well-known target of Rac1 molecule. 41,[60][61][62] Nonetheless, it is conceivable that a tightly regulated TNFα-Rac1-P38 signaling cascade is essential for uterine luminal epithelium clearance during postimplantation uterine development.…”

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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“…Apoptosis, a genetic program leading to cell death, is evident in the inner cell mass of late pre-implantation embryos and epiblastic cores of early post-implantation embryos in vivo (14). Additionally, mESCs are irreversibly committed to differentiation upon LIF withdrawal, and parts of the cells undergo apoptosis during in vitro differentiation (15).…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Jeong

Cha

et al. 2007

Journal of Biological Chemistry

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During mammalian embryogenesis, the early embryo grows in a relatively hypoxic environment due to a restricted supply of oxygen. The molecular mechanisms underlying modulation of self-renewal and differentiation of mouse embryonic stem cells (mESCs) under such hypoxic conditions remain to be established. Here, we show that hypoxia inhibits mESC self-renewal and induces early differentiation in vitro, even in the presence of leukemia inhibitory factor (LIF). These effects are mediated by down-regulation of the LIF-STAT3 signaling pathway. Under conditions of hypoxia, hypoxia-inducible factor-1␣ (HIF-1␣) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter. Ectopic expression and small interference RNA knockdown of HIF-1␣ verified the inhibitory effect on LIFR transcription. Our findings collectively suggest that hypoxia-induced in vitro differentiation of mESCs is triggered, at least in part, by the HIF-1␣-mediated suppression of LIF-STAT3 signaling. Analysis of mESCs2 isolated from the inner cell mass of preimplantation embryos has aided in elucidating the early molecular events and mechanisms responsible for maintenance of ESC pluripotency (1). In contrast to human ESCs (hESCs), selfrenewal of mESCs can be sustained indefinitely in feeder-free conditions if supplemented with LIF (2). mESC lines can be derived directly from embryos in the presence of LIF, indicating that this factor is specifically required for the maintenance of pluripotency. Intracellular signaling cascades initiated by LIF are mediated through the heterodimerization of LIFR and glycoprotein 130 (gp130). This complex activates Janus-associated tyrosine kinase and the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Activation of STAT3 by LIF is crucial in mediating self-renewal signals in mESCs (3, 4).During mammalian development, oxygen needed for cellular metabolism in the early embryo is supplied by simple diffusion from fluids within the oviduct and uterus. Thus, the early embryo develops in a relatively hypoxic environment until the onset of vascularization after implantation (5). Actually, oxygen tension in the mammalian reproductive tract is reported to be less than half the atmospheric oxygen tension (6). Low oxygen tension triggers a wide range of cellular events centered on the regulation of hypoxia-inducible factor-1 (HIF-1) (7), which consists of a common ␤ subunit (HIF-1␤) and an oxygen-sensitive ␣ subunit (HIF-1␣). Under normoxia, HIF-1␣ is rapidly degraded via the von Hippel-Lindau protein-mediated ubiquitin-proteasome pathway (8). Although the role and biological relevance of HIF-1 during murine embryonic development have been established (9 -11), our understanding of how HIF-1 affects the early differentiation of mESCs at the molecular level is beginning to emerge.Our previous study demonstrated the presence of hypoxic regions during normal mouse development (12), which prompted us to study the role of hy...

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“…Thus, epithelial apoptosis occurs due to the absence of epithelial ERα. Interestingly, normal regulation of apoptosis has been shown to be important for implantation (44). Therefore, alteration of growth and apoptosis as a result of the loss of uterine epithelial ERα leads to the infertility phenotype in UtEpiαERKO.…”

Section: Discussionmentioning

confidence: 99%

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Winuthayanon

Hewitt

Orvis

et al. 2010

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

213

243

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Female fertility requires estrogen to specifically stimulate estrogen receptor α (ERα)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ERα in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERα knockout (UtEpiαERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ERα in uterine epithelium, and female UtEpiαERKO are infertile. Herein, we demonstrate that 17β-estradiol (E 2 )-induced uterine epithelial proliferation was independent of uterine epithelial ERα because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpiαERKO uteri after E 2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wildtype (WT) and UtEpiαERKO and mimicked the E 2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERα was necessary to induce lactoferrin, an E 2 -regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERα did not alter the E 2 -dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpiαERKO had robust evidence of apoptosis after 3 d of E 2 treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ERα in the proliferative response, but ERα is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERα in uterine tissue and its contribution during pregnancy.conditional knockout | paracrine regulation

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Apoptosis at the time of embryo implantation in mouse and rat

Cited by 121 publications

References 137 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

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

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