Gain-of-function β-catenin in the uterine mesenchyme leads to impaired implantation and decidualization.
Embryo implantation and endometrial decidualization are critical events that occur during early pregnancy in humans and mice, and perturbation in either can result in infertility. WNT signaling through the canonical β-catenin pathway plays a pivotal role in embryonic Müllerian duct development, postnatal uterine maturation and establishment of pregnancy. Loss of β-catenin in the Müllerian duct mesenchyme (MDM)-derived stroma and myometrium results in impaired decidualization and infertility, whereas gain-of-function (GOF) results in the formation of mesenchymal tumors and sub-fertility attributed to malformed oviducts. We hypothesized that GOF β-catenin further contributes to sub-fertility through improper stromal and epithelial cell signaling during embryo implantation and decidualization. We show that mice with GOF β-catenin in MDM-derived stroma and myometrium have reduced implantation sites after embryo transfer and decreased decidualization. On day 4.5 of pseudopregnancy or in mice treated with progesterone and estrogen to mimic early pregnancy, the estrogen-LIF-ERK and progesterone-IHH pathways remain predominantly intact in GOF β-catenin mice; however, JAK/STAT signaling is altered. pSTAT3 is significantly reduced in GOF β-catenin mice and expression of downstream epithelial junctional complex factors,Ctnna1andCldn1, is increased. We also show that purified stromal cells from GOF β-catenin uteri, when removed from epithelial cell influence and provided with the appropriate hormonal stimuli, are able to decidualizein vitroindicating that the cells are intrinsically capable of decidualization. Taken together, these results suggest that dysregulated β-catenin activity in the stroma affects epithelial cell STAT3 signaling and ultimately embryo implantation and stromal decidualization.
Department of ObstetricsGynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
Amanda L
AL
Patterson
Department of ObstetricsGynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
Jamieson
J
Pirochta
Department of ObstetricsGynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA.
Stephanie Y
SY
Tufano
Department of ObstetricsGynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA jose.teixeira@hc.msu.edu.
Jose M
JM
Teixeira
D000818:Animals; D003656:Decidua / Q000187:drug effects / Q000378:metabolism*; D010064:Embryo Implantation / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology; D011555:Pseudopregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D050796:STAT3 Transcription Factor; D051176:beta Catenin; D011374:Progesterone; D004958:Estradiol
STAT3; decidualization; embryo implantation; stromal–epithelial crosstalk; β-catenin