(197) Progesterone Receptor Regulates Post-Implantation Decidual-Trophoblast Interactions and Placental Development

Shu-Yun Li¹, Francesco J. DeMayo¹

1. Reproductvie and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

Abstract Text:  
Progesterone receptor (PGR) plays a critical role in pregnancy, particularly in regulating uterine function and decidualization. While its role in early pregnancy and implantation is well-documented, its function in post-implantation remains less understood. Decidualization is a crucial process essential for establishing a receptive maternal environment and facilitating proper trophoblast invasion and differentiation. In aging mice, which exhibit reduced PGR and phosphorylated STAT3 (pSTAT3) levels in uterine stromal cells, defects in decidualization led to impaired placental development, characterized by a thinner labyrinth layer, defective spongiotrophoblast (SpT) formation, disrupted giant cell (GC) differentiation and localization, and an increased tendency toward trophoblast giant cell (TGC) lineage differentiation. Such abnormalities likely result from impaired communication between the decidua and trophoblast compartments. However, the precise molecular and cellular mechanisms underlying this communication remain unclear.
To investigate the role of PGR in post-implantation, we employed a temporally controlled tamoxifen-inducible Pgr^CreERT2 mouse model, enabling conditional deletion of PGR at a specific gestational timepoint. We utilized 4-hydroxytamoxifen (4-OHT), a more potent alternative to tamoxifen, to induce Cre recombination. Given the potential adverse effects of tamoxifen administration during early pregnancy, we conducted a pilot study in which a single dose of 4-OHT was administered at gestational day (GD) 8.5.  We determined an optimal dosage that did not affect placental weight, gestation period, or litter size. When crossed with Rosa26-SUN1 reporter mice, SUN1 expression was strongly detected in PGR-expressing cells in the mesometrium from GD9.5 to GD11.5, indicating that the Cre-mediated recombination effectively occurred in PGR-expressing cells. Therefore, 4-OHT was administered at GD8.5 to knockout PGR using Pgr^CreERT2;flox mice. At GD9.5, the strong PGR expression was deleted in the whole uterus, and by GD10.5, its deletion was specifically observed in the region adjacent to trophoblast compartments in the mesometrium. Subsequent analysis revealed that PGR deletion induced post-implantation defects reminiscent of age-related phenotypes observed in older mice. Specifically, placentas from tamoxifen-induced PGR knockout (_TamPGRKO) mice exhibited a smaller and malformed labyrinth layer, an increased number of TGCs, and impaired trophoblast invasion. Notably, these defects led to embryonic lethality beyond GD14.5. These results suggest that PGR is indispensable for maintaining proper decidual-trophoblast interactions and ensuring correct lineage differentiation and invasion in the placenta.
Our findings reveal the critical role of PGR in post-implantation pregnancy, particularly in modulating the intricate crosstalk between maternal decidua and trophoblast compartments. The similarities between the age-related phenotypes and tamoxifen-induced PGR knockout suggest a potential link between declining PGR function and placental insufficiency in aging pregnancies. Moreover, we developed an in vivo mouse model for studying gene functions in post-implantation, providing a valuable tool to investigate molecular mechanisms regulating maternal-fetal interactions and placental development.