Nuclear Orphan Receptor, COUP-TFII, in Reproduction.

COUP-TFII is an orphan nuclear receptor of the nuclear receptor superfamily. COUP-TFII is highly expressed in the uterine stroma and its expression is controlled by progesterone-Ihh-Ptch signaling from the epithelium to the stroma. Mutants with uterine-specific deletion of COUP-TFII are defective in embryo attachment and decidualization, phenotypes similar to mutant mice with the conditional ablation of Ihh or PR. Our results indicate that COUP-TFII is a downstream target of Indian hedgehog that mediates PR/hedgehog signaling to regulate embryo attachment and decidualization. Interestingly, the expression of estrogen receptor target genes in the epithelium is enhanced in the absence of COUP-TFII, suggesting COUP-TFII may mediate progesterone signaling to repress estrogen receptor activity. To assess this, the mutants were treated with ICI 182,780 to determine if receptivity could be restored by the inhibition of estrogen activity. Intriguingly, the implantation sites are partially restored upon ICI 182,780 treatment. Also, the rescued mice exhibited decidualization by expressing markers BMP2 and Wnt4. Our findings reveal that COUP-TFII mediates progesterone signaling to inhibit estrogen receptor activity and establish the requirement for epithelial-stroma interactions during the implantation process. In addition to COUP-TFII's role in the stroma, we found that COUP-TFII is also expressed in the myometrium. Deletion of COUP-TFII in the smooth muscle results in leiomyoma-like ectopic tissues. The ectopic tissues express smooth muscle actin and collagen, characteristic markers of leiomyoma. The development of leiomyoma may be associated with improper wound repair processes in the COUP-TFII deficient mice. Since leiomyoma is one of the most common benign tumors in the female reproductive tract, our findings provide a new perspective on women's health care associated with dysfunction of COUP-TFII. This work is supported by U54 HD 07495, Project 4, HL076448 and DK 62434. (platform)