Primary decidual zone formation requires Scribble for pregnancy success in mice

Yuan, Jia; Aikawa, Shizu; Deng, Wenbo; Bartos, Amanda; Walz, Gerd; Grahammer, Florian; Huber, Tobias B.; Sun, Xiaofei; Dey, Sudhansu K.

doi:10.1038/s41467-019-13489-4

Cited by 52 publications

(41 citation statements)

References 43 publications

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“…Uterine epithelium and stroma are two major components of the endometrium, and their interactions are involved in the process of the receptivity acquisition 1,18,19 . Uterine epithelium and stroma have independent and mutual functions to support uterine receptivity and embryo implantation 1,[18][19][20] . Although the previous literature demonstrated the significance of uterine STAT3 in embryo implantation 14 , the role of epithelial and stromal STAT3 in the process of embryo implantation remains unclear.…”

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Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

Hiraoka

Hirota

Fukui

et al. 2020

Sci Rep

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Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.

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Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

Hiraoka

Hirota

Fukui

et al. 2020

Sci Rep

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“…The finding that macrophages remain close to Cnr1 -/- Cnr2 -/- implantation chambers prompted us to examine the formation of the PDZ on day 6 of pregnancy. PDZ formation requires Scrib signaling ( Yuan et al, 2019 ), yet the Scrib positive domain is much reduced in Cnr1 -/- Cnr2 -/- females ( Figure 4a ). This result is also supported by the presence of blood vessels, revealed by immunostaining of FLK1, a reliable marker of blood vessels, in the Cnr1 -/- Cnr2 -/- PDZ on day 6 of pregnancy ( Figure 4b ).…”

Section: Resultsmentioning

confidence: 99%

“…Because the PDZ is avascular, this zone is normally devoid of maternal immune cells, and protects embryos from circulating maternal insults ( Tung et al, 1986 ). Recently we have shown that Scribble (Scrib), a scaffold protein and a component of the planar cell polarity (PCP), plays a key role in PDZ formation ( Yuan et al, 2019 ). However, molecular regulation in the formation of the PDZ is still far from clear.…”

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Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

Dewar

Kim

et al. 2020

eLife

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With implantation mouse stromal cells begin to transform into epithelial-like cells surrounding the implantation chamber forming an avascular zone called the primary decidual zone (PDZ). In mouse, the PDZ forms a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents. The process of decidualization is critical for early pregnancy maintenance in mice and humans. Mice deficient in cannabinoid receptors, CB1 and CB2, show compromised PDZ with dysregulated angiogenic factors, resulting in the retention of blood vessels and macrophages. This phenotype is replicated in Cnr1-/-, but not in Cnr2-/- mice. In vitro decidualization models suggest that Cnr1 levels substantially increase in mouse and human decidualizing stromal cells, and that neutralization of CB1 signaling suppresses decidualization and misregulates angiogenic factors. In sum, we propose that implantation quality depends on appropriate angiogenic events driven by the integration of CB2 in endothelial cells and CB1 in decidual cells.

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“…On D4, in the P4-primed uterus, E2 regulates new functions essential for embryo implantation; these are the expression of glandular Lif which is viewed as the final step in the acquisition of uterine receptivity and which, together with P4, E2 induces stromal cell proliferation and decidualization (7,53,54). Stromal cell decidualization begins on the afternoon of D5 in cells surrounding the implantation chamber in the antimesometrial region of the uterus; this forms the primary decidual zone (PDZ), a transient tissue that is well developed by D6 but has undergone demise by D8 (55)(56)(57)(58). This PDZ is avascular and is enriched in intercellular tight junctions, gap junctons, and adherens junctions, and it creates a permeability barrier around the implantation chamber, isolating the embryo from immune cells and harmful molecules present in the maternal circulation (59,60).…”

Section: Discussionmentioning

confidence: 99%

Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells

et al. 2020

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Objective: To characterize the expression and signaling of uterine GPR83 in vivo in the nonpregnant and pregnant mouse and in vitro in human endometrial and nonendometrial cells. Design: Controlled laboratory study. Setting: Not applicable. Patients: Not applicable. Interventions: None. Main Outcome Measures: Expression of uterine Gpr83 was determined by quantitative polymerase chain reaction throughout the estrous cycle and during early pregnancy in ovarian-stimulated and nonÀovarian-stimulated mice and pregnant and pseudopregnant mice. Expression was also determined in ovariectomized mice after the administration of oil, E2, P4, or E2 þ P4 and in stromal cells following 6 days of in vitro decidualization. GPR83 signaling was studied in human endometrial and embryonic kidney cell lines. Cells were treated by PEN, a GPR83 ligand, and PEN-induced extracellular signal-regulated kinase (ERK) phosphorylation was assayed under conditions that blocked Ga q/11 and/or b-arrestin signaling. Results: Uterine Gpr83 is expressed throughout the estrous cycle and during early pregnancy; expression increases dramatically at the time of uterine receptivity, embryo implantation, and stromal cell decidualization. In the ovariectomized mouse, hormone add-back reveals that Gpr83 expression is highly responsive to the combined treatment of E2 and P4, and studies in the ovarian-stimulated mouse show that expression is also very sensitive to changes in E2 and P4 and is therefore tightly regulated by E2 and P4. At the implantation site, expression is elevated up to D6 of pregnancy and then declines rapidly on D7 and D8, suggesting that if there is any involvement in decidualization, it is likely associated with primary but not secondary stromal cell decidualization. This premise was supported by the observation that stromal cell decidualization in vitro progresses with a decline in Gpr83 expression. In ERa/ PR-expressing endometrial Ishikawa cells, GPR83 mediates PEN signals in a Ga q/11-dependent manner, and studies conducted in HEK 293 cells lacking b-arrestin revealed that GPR83 also signals via a b-arrestinÀdependent manner. When signaling by either one or both pathways is downregulated, cells exhibit a major reduction in responsiveness to PEN treatment, demonstrating that signaling by both pathways is significant. Conclusion: We hypothesize that PEN/GPR83 signaling regulates uterine receptivity, embryo implantation, and primary stromal cell decidualization by coupling to Ga q/11-and b-arrestinÀdependent pathways.

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Primary decidual zone formation requires Scribble for pregnancy success in mice

Cited by 52 publications

References 43 publications

Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

Differential roles of uterine epithelial and stromal STAT3 coordinate uterine receptivity and embryo attachment

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

Uterine Gpr83 mRNA is highly expressed during early pregnancy and GPR83 mediates the actions of PEN in endometrial and non-endometrial cells

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