Porcupine-dependent Wnt signaling controls stromal proliferation and endometrial gland maintenance through the action of distinct WNTs

Farah, Omar; Biechele, Steffen; Rossant, Janet; Dufort, Daniel

doi:10.1016/j.ydbio.2016.11.023

Cited by 16 publications

(9 citation statements)

References 58 publications

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“…However, we were unable to find any evidence of enhanced CTNNB1 expression. Consistent with this, the phenotypic changes observed in the reproductive tracts of Lats1 flox/flox ; Lats2 flox/flox ; Amhr2 cre/+ mice appeared completely unrelated to those in any previously reported mouse models in which WNT signaling was altered in the Müllerian duct (Dunlap et al, 2011;Farah et al, 2017;Franco et al, 2011;Mericskay et al, 2004;Prunskaite-Hyyrylainen et al, 2016;St-Jean et al, 2019;Vainio et al, 1999). Inactivation of Hippo in Lats1 flox/flox ; Lats2 flox/flox ; Amhr2 cre/+ mice did, however, clearly result in the activation of the canonical Hippo effectors YAP and TAZ, as shown by their increased expression, along with that of their transcriptional target genes.…”

Section: Discussionsupporting

confidence: 79%

“…Moreover, deletion of the Wnt7a gene results in a partially posteriorized female reproductive tract, with uterus-like oviducts and a uterus with histological characteristics of the vagina (Dunlap et al, 2011). Wnt4, Wnt5a and Wnt7a have also all been implicated in uterine gland formation (Dunlap et al, 2011;Farah et al, 2017;Franco et al, 2011;Mericskay et al, 2004;St-Jean et al, 2019). Although the signaling processes whereby WNT ligands direct the development of the female reproductive tract are poorly understood, the canonical WNT signaling effector β-catenin (CTNNB1) is believed to play an important role, largely based on phenotypic abnormalities observed in Ctnnb1 conditional knockout models that mimic to some extent those observed in knockout models of specific WNT genes (Deutscher and Hung-Chang Yao, 2007;Hernandez Gifford et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme

et al. 2019

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WNT signaling plays essential roles in the development and function of the female reproductive tract. Although crosstalk with the Hippo pathway is a key regulator of WNT signaling, whether Hippo itself plays a role in female reproductive biology remains largely unknown.Here, we show that conditional deletion of the key Hippo kinases Lats1 and Lats2 in mouse Müllerian duct mesenchyme cells caused them to adopt the myofibroblast cell fate, resulting in profound reproductive tract developmental defects and sterility. Myofibroblast differentiation was attributed to increased YAP and TAZ expression (but not to altered WNT signaling), leading to the direct transcriptional upregulation of Ctgf and the activation of the myofibroblast genetic program. Müllerian duct mesenchyme cells also became myofibroblasts in male mutant embryos, which impeded the development of the male reproductive tract and resulted in cryptorchidism. The inactivation of Lats1/2 in differentiated uterine stromal cells in vitro did not compromise their ability to decidualize, suggesting that Hippo is dispensable during implantation. We conclude that Hippo signaling is required to suppress the myofibroblast genetic program and maintain multipotency in Müllerian mesenchyme cells.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme

et al. 2019

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“… 42 Studies also manifested that Wnt/ β -catenin signaling pathway was involved in embryo implantation, stromal proliferation, deciduation and gland maintenance. 43 , 44 Monhamed et al 45 reported that Wnt/ β -catenin signaling was first transiently activated in the uterine luminal epithelium at the prospective site of implantation in mouse. Here, we found that decreased LeY by miR-200c mimics transfection or LeY antibody blocking on CD44 inactivated Wnt/ β -catenin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200c impairs uterine receptivity formation by targeting FUT4 and α1,3-fucosylation

et al. 2017

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Successful embryo implantation requires the establishment of a receptive endometrium. Poor endometrial receptivity has generally been considered as a major cause of infertility. Protein glycosylation is associated with many physiological and pathological processes. The fucosylation is catalyzed by the specific fucosyltransferases. Fucosyltransferase IV (FUT4) is the key enzyme for the biosynthesis of α1,3-fucosylated glycans carried by glycoproteins, and the previous studies showed FUT4 expression changed dynamically during perimplantation. MicroRNAs (miRNAs) are known to regulate specific gene expression. However, the relationship between specific miRNA and FUT4, as well as the role of miRNA/FUT4 in the establishment of uterine receptivity remains elusive. In the current study, we reported that the levels of miR-200 family members were significantly increased in serum from infertility and abortion patients relative to healthy non-pregnancy and early-pregnancy women. Among these, miR-200c was the most sensitive diagnostic criterion for infertility by receiver operating characteristic curve analysis. FUT4 was lower in the serum from infertility and abortion patients compared with the healthy non-pregnancy and early-pregnancy women. Using endometrial cell lines and a mouse model, we demonstrated that miR-200c targeted and inhibited FUT4 expression, leading to the dysfunction of uterine receptivity. Our results also revealed that miR-200c decreased α1.3-fucosylation on glycoprotein CD44, which further inactivated Wnt/β-catenin signaling pathway. Taken together, miR-200c hampers uterine receptivity formation by targeting FUT4 and α1.3-fucosylation on CD44. miR-200c and FUT4 may be applied together as the potential markers for endometrial receptivity, and useful diagnostic and therapeutic targets for infertility.

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“…In recent years, a variety of genetically engineered mouse models have helped us identify many crucial genes contributing to uterine adenogenesis, including Foxa2, Wnt7a, Lgr4 and Dlx5/6. 4,6,[8][9][10][11][12][13] However, potential contribution of epigenetic regulators during uterine adenogenesis remains mysterious and barely explored yet.…”

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confidence: 99%

PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice

Cui

Kong

et al. 2017

Cell Death Differ

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Formation of secretary endometrial glands in the uterus known as adenogenesis is a typical process of branching morphogenesis involving dynamic epithelial growth and differentiation. Unsuccessful adenogenesis often leads to female infertility. However, it remains largely unexplored so far regarding the epigenetic machinery governing normal endometrial gland formation. Here, we demonstrated that PR-Set7, an epigenetic regulator for H4K20me1 modification, was extensively expressed in the postnatal uteri, and its conditional deletion resulted in a complete lack of endometrial glands and infertility in mice. Subsequent analysis revealed that uterine PR-Set7 deficiency abolishes the dynamic endometrial epithelial population growth during the short span of gland formation from postnatal days 3 to 9. This markedly reduced epithelial population growth in PR-Set7-null mutant uteri is well associated with DNA damage accumulation and massive apoptotic death in the epithelium, due to blockade of 53BP1 recruitment to DNA damage sites upon reduced levels of H4K20me1/2. Using Pgr/Rosa26 mouse line and postnatal progesterone injection mouse model, we further confirmed that an impaired epithelial cell population growth either by inducing epithelial death in the diphtheria toxin-A (DTA)-mouse model or attenuating epithelial growth upon postnatal progesterone treatment similarly hampers uterine adenogenesis. Collectively, we establish here a novel 'epithelial population growth threshold' model for successful gland development. Besides further shedding light on the regulatory machinery governing uterine gland formation, our findings raise a safety concern on progesterone supplementation to prevent preterm birth in women bearing a female fetus, as exogenous progesterone may hamper uterine adenogenesis via attenuating epithelial population growth.

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Porcupine-dependent Wnt signaling controls stromal proliferation and endometrial gland maintenance through the action of distinct WNTs

Cited by 16 publications

References 58 publications

Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme

Lats1 and Lats2 are required for the maintenance of multipotency in the Müllerian duct mesenchyme

MicroRNA-200c impairs uterine receptivity formation by targeting FUT4 and α1,3-fucosylation

PR-Set7 deficiency limits uterine epithelial population growth hampering postnatal gland formation in mice

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