A Positive Feedback Loop Involving Gcm1 and Fzd5 Directs Chorionic Branching Morphogenesis in the Placenta

Lu, Jinhua; Zhang, Shuang; Nakano, Hitoo; Simmons, David G.; Wang, Shumin; Kong, Shuangbo; Wang, Qiang; Shen, Lianju; Tu, Z. C.; Wang, Weixiang; Wang, Bingyan; Wang, Hongmei; Wang, Yanling; Es, Johan H. van; Clevers, Hans; Leone, Gustavo; Cross, James C.; Wang, Haibin

doi:10.1371/journal.pbio.1001536

Cited by 90 publications

(89 citation statements)

References 43 publications

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“…In situ hybridization was performed as previously described. 64,65 Mouse-specific cRNA probes for Rac1, Areg, Muc1, Ltf, Lif, Hoxa-10 and Wnt5a were used for hybridization. Cryosections hybridized with sense probes served as negative controls.…”

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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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: 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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“…For immunofluorescence staining, 4% formaldehyde-fixed Ishikawa cells were incubated with anti-BMI1, -HA, and -flag antibodies. Specific secondary antibodies were utilized to detect the antigen and DAPI was applied to identify cell nuclei (44). The images were captured by using a Leica DM2500 light microscope.…”

Section: Animals and Treatments Bmi1mentioning

confidence: 99%

“…Protein extraction and Western blot analysis were performed as described previously (44). Antibodies against BMI1, RING1A, RING1B, E6AP, H2AK119Ub, ERα, PR, flag, HA, FKBP52, β-actin, Myc, ubiquitin, and His were used.…”

Section: Animals and Treatments Bmi1mentioning

confidence: 99%

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation

Xin¹,

Kong²,

Yan³

et al. 2017

Journal of Clinical Investigation

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“…Homozygous deletion of Wnt2 in mice results in defective placental labyrinth formation (25). The Wnt receptor, Fzd5, which is predominantly expressed by SynT cells within the labyrinth of mouse placenta, is critical for normal labyrinth development and maintenance of Gcm1 expression (26). miR-518f is predicted to target HSD17B1, which metabolizes estrone to estradiol and plays an important role in placental vascular development (27).…”

Section: Expression Of C19mc Members Is Decreased During Differentiatmentioning

confidence: 99%

Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia

Zhang

Muralimanoharan

Wortman

et al. 2016

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

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Dysregulation of human trophoblast invasion and differentiation can result in preeclampsia (PE), a hypertensive disorder of pregnancy with significant morbidity and mortality for mother and offspring. miRNA microarray analysis of RNA from human cytotrophoblasts (CytT), before and after differentiation to syncytiotrophoblast (SynT) in primary culture, revealed that members of miR-515 family-including miR-515-5p, miR-519e-5p, miR-519c-3p, and miR-518f, belonging to the primate-and placenta-specific chromosome 19 miRNA cluster (C19MC)-were significantly down-regulated upon human SynT differentiation. The proto-oncogene, c-MYC, which declines during SynT differentiation, interacted with E-boxes upstream of pri-miR-515-1 and pri-miR-515-2, encoding these mRNAs, to enhance their expression. Predicted targets of miR-515-5p, known to be critical for human SynT differentiation, including hCYP19A1/aromatase P450, glial cells missing 1 (GCM1), frizzled 5 (FZD5), WNT2, Sp1, and estrogen receptor-α (ERα) mRNA, were markedly up-regulated during SynT differentiation. Notably, overexpression of miR-515-5p in cultured primary human trophoblasts impaired SynT differentiation and specifically decreased expression of hCYP19A1, GCM1, and Fzd5, which were validated as its direct targets. Interestingly, miR-515-5p levels were significantly increased in PE placentas, whereas mRNA and protein levels of targets, hCYP19A1, GCM1, and FZD5, were significantly decreased, compared with placentas of normotensive women. Thus, miR-515-5p may serve a key role in human trophoblast differentiation; its aberrant up-regulation may contribute to the pathogenesis of PE.human placenta | differentiation | miRNAs | aromatase | Wnt signaling

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A Positive Feedback Loop Involving Gcm1 and Fzd5 Directs Chorionic Branching Morphogenesis in the Placenta

Abstract: Placenta formation during pregnancy requires chorioallantoic branching morphogenesis that involves establishing an amplifying feedback loop between Frizzled5 and Gcm1 to regulate branching initiation and trophoblast differentiation.

Cited by 90 publications

References 43 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

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation

Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia

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