COUP-TFII Mediates Progesterone Regulation of Uterine Implantation by Controlling ER Activity

Abstract

Progesterone and estrogen are critical regulators of uterine receptivity. To facilitate uterine remodeling for embryo attachment, estrogen activity in the uterine epithelia is attenuated by progesterone; however, the molecular mechanism by which this occurs is poorly defined. COUP-TFII (chicken ovalbumin upstream promoter transcription factor II; also known as NR2F2), a member of the nuclear receptor superfamily, is highly expressed in the uterine stroma and its expression is regulated by the progesterone–Indian hedgehog–Patched signaling axis that emanates from the epithelium. To further assess COUP-TFII uterine function, a conditional COUP-TFII knockout mouse was generated. This mutant mouse is infertile due to implantation failure, in which both embryo attachment and uterine decidualization are impaired. Using this animal model, we have identified a novel genetic pathway in which BMP2 lies downstream of COUP-TFII. Epithelial progesterone-induced Indian hedgehog regulates stromal COUP-TFII, which in turn controls BMP2 to allow decidualization to manifest in vivo. Interestingly, enhanced epithelial estrogen activity, which impedes maturation of the receptive uterus, was clearly observed in the absence of stromal-derived COUP-TFII. This finding is consistent with the notion that progesterone exerts its control of implantation through uterine epithelial-stromal cross-talk and reveals that stromal-derived COUP-TFII is an essential mediator of this complex cross-communication pathway. This finding also provides a new signaling paradigm for steroid hormone regulation in female reproductive biology, with attendant implications for furthering our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in such human reproductive disorders as endometriosis and endometrial cancer.

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

“…3 A and B). The expressions of Pgr-regulated genes Indian hedgehog (Ihh) (18), amphiregulin (Areg) (19), homobox A10 (Hoxa10) (20), nuclear receptor subfamily 2, group F, member 2 (Nr2f2) (18), and heart and neural crest derivatives expressed transcript 2 (Hand2) (21) were significantly decreased, and E2 target genes mucin 1 (Muc1), Muc4, lactotransferrin (Ltf), and complement component 3 (C3) (21,22) were significantly increased in OEx mice compared with control mice (Fig. 3 C and D).…”

“…S4D). Exogenous hormones (P4 and E2) were used to prime the uterus of ovariectomized mice to mimic the receptivity of the uterus at 3.5 dpc, independent of the effects of ovarian factors (22). This treatment was capable of inducing a decidualization response after an artificial stimulation.…”

Molecular cues to the anti-implantation effect of nano-puerarin in rats

“…One of the major attributes of P 4 action is to regulate the epithelial oestrogen action tightly. Importantly, P 4 by acting via stromal PGR attenuates the oestrogeninduced epithelial gene expression (Kurihara et al 2007). Thus, P 4 elicits stromal cell decidualization via Ihh-Nr2f2-Bmp2 signalling.…”

“…The endometrium differentiates into an altered state when the blastocysts are capable of mediating effective two-way communication to initiate the process of implantation (Dey et al 2004). The molecular mechanism underlying this interaction is poorly defined; however, a novel signalling pathway involving Ihh-Nr2f2-Bmp2 has been implicated in the process (Kurihara et al 2007). The Pgr-knockout mouse model demonstrated that Figure 9 Working model of PN in mediating anti-decidualizing effect.…”

“…Ihh has been identified as an acute PGR target gene (Kurihara et al 2007). It transduces its signal via the expression of stromal Nr2f2 that in turn regulates decidualization through its major downstream effector, Bmp2 (Kurihara et al 2007). The shreds of evidence provided herein attest that puerarin efficiently ablates the Ihh-Nr2f2-Bmp2 pathway and induces loss of uterine potential for decidualization.…”