CDX2 downregulation in mouse mural trophectoderm during peri‐implantation is heteronomous, dependent on the YAP‐TEAD pathway and controlled by estrogen‐induced factors

Purpose To investigate the transition of CDX2 expression patterns in mouse trophectoderm (TE) and its regulatory mechanisms during implantation. Methods Mouse E3.5-4.5 blastocysts were used to immunostain CDX2, YAP, TEAD4, and ESRRB. Endogenous estrogen signaling was perturbed by administrating estrogen receptor antagonist ICI 182,780 or ovariectomy followed by administration of progesterone and beta-estradiol to elucidate the relationship between the transition of CDX2 expression patterns and ovarian estrogen-dependent change in the uterine environment. Results CDX2 expression was gradually downregulated in the mural TE from E4.0 in vivo, whereas CDX2 downregulation was not observed in blastocysts cultured in KSOM. Fetal bovine serum (FBS) supplementation in KSOM induced CDX2 downregulation independently of blastocyst attachment to dishes. CDX2 downregulation in the mural TE was repressed by administration of ICI 182,780 or by ovariectomy, and administration of beta-estradiol into ovariectomized mice retriggered CDX2 downregulation. Furthermore, Cdx2 expression in the mural TE might be controlled by the YAP-TEAD pathway. Conclusions CDX2 downregulation was induced heteronomously in the mural TE from E4.0 by uterus-derived factors, the secretion of which was stimulated by ovarian estrogen.