The uterus plays an essential role in the reproductive health of women and controls critical processes such as embryo implantation, placental development, parturition, and menstruation. Progesterone receptor (PR) regulates key aspects of the reproductive function of several mammalian species by directing the transcriptional program in response to progesterone (P4). P4/PR signaling controls endometrial receptivity and decidualization during early pregnancy and is critical for the establishment and outcome of a successful pregnancy. PR is also essential throughout gestation and during labor, and it exerts critical roles in the myometrium, mainly by the specialized function of its two isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), which display distinct and separate roles as regulators of transcription. This review summarizes recent studies related to the roles of PR function in the decidua and myometrial tissues. We discuss how PR acquired key features in placental mammals that resulted in a highly specialized and dynamic role in the decidua. We also summarize recent literature that evaluates the myometrial PR-A/PR-B ratio at parturition and discuss the efficacy of current treatment options for preterm birth.

The biological processes that control endometrial receptivity and embryo implantation are critical for the successful outcome of pregnancy. The endometrium is the complex inner lining of the uterine wall that is under the cyclical control of estrogen and progesterone and is a site of intimate contact between mother and blastocyst. The bone morphogenetic signaling (BMP) pathway is a highly conserved signaling pathway that controls key cellular processes throughout pregnancy and exerts intracellular effects via the SMAD1/5 transcription factors. To delineate the endometrial compartment-specific roles of BMP signaling, we generated mice with epithelial-specific conditional deletion of SMAD1/5 using Lactoferrin-icre (Smad1flox/flox;Smad5flox/flox;Lactoferrin-cre, “Smad1/5 cKO”). Histological analysis of the reproductive tracts showed that Smad1/5 cKO mice were developmentally normal and displayed no defects in glandular morphology. In fertility analyses, single SMAD1 or SMAD5 deletion had no effect on fertility, however, double conditional deletion of SMAD1 and SMAD5 resulted in severe subfertility. Timed mating analyses revealed endometrial receptivity defects in the Smad1/5 cKO mice beginning at 3.5 days post coitum (dpc) that perturbed embryo implantation at 4.5 dpc, as demonstrated by the detection of unattached blastocysts in the uterus, decreased COX2 expression, and FOXO1 cytoplasmic mis-localization. We also found that defects that arose during peri-implantation adversely affected embryonic and decidual development at 5.5 and 6.5 dpc. Thus, uterine epithelial BMP/SMAD1/5 signaling is essential during early pregnancy and SMAD1/5 epithelial-specific deletion has detrimental effects on stromal cell decidualization and pregnancy development.

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFβ family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids were used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre developed endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determined that genetic or pharmacological inhibition of SMAD2/3 signaling disrupted organoid morphology, increased the glandular and secretory cell markers, FOXA2 and MUC1, and altered the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids revealed elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFβ family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.

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