BMP/SMAD1/5 Signaling in the Endometrial Epithelium Is Essential for Receptivity and Early Pregnancy

Abstract

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.

Assessment of BMP7, SMAD4, and CDH1 Expression Profile and Regulatory miRNA-542-3p in Eutopic and Ectopic Endometrium of Women with Endometriosis

“…Several studies have focused on the importance of BMP/SMAD signaling in endometriosis [ 41 , 61 , 62 ] as well as on the role of miRNA in the development and progression of the disease [ 57 , 58 , 63 , 64 ]. Among the many candidates, one potentially interesting miRNA is miR-542-3p, for which a suppressor function in tumor development is well characterized.…”

Affinity-tagged SMAD1 and SMAD5 mouse lines reveal transcriptional reprogramming mechanisms during early pregnancy

“…Published studies have shown that nuclear SMAD1/5 localize to the stroma and epithelium during the decidualization process at 4.5 dpc, during the window of implantation 9 . Conditional deletion of SMAD1/5 exclusively in the uterine epithelium using lactoferrin-icre ( Ltf -icre) results in severe subfertility due to impaired implantation and decidual development 100 . Conditional deletion of SMAD1/5/4 exclusively in the cells from mesenchymal lineage (including uterine stroma) using anti-Mullerian hormone type 2 receptor cre ( Amhr2-cre ) results in infertility with defective decidualization 91,92 .…”

Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface

“…53,54 In addition to showing that BMPs exert their signals via a cell surface receptor complex, recent studies have shown that the transcription factors SMAD1 and SMAD5 are required to complete the decidualization process in response to BMPs within the endometrium. [55][56][57] Hence, BMP signaling, via the ALK2 and ALK3 receptors and the SMAD1/SMAD5 transcription factors, is critical for reprogramming endometrial stroma into functional decidua during early pregnancy. 49 Conditional uterine SMAD1/5 knock-out using PR-cre mouse model results in sterile females due to embryo implantation defects caused by cystic endometrial glands, endometrial hyperproliferation during the window of implantation, and faulty apicobasal transformation Monsivais et al 55 Epithelial-specific conditional double knock-out of SMAD1 and SMAD5 results in subfertility linked to impaired endometrial receptivity, delayed implantation, and peri-implantation defects Tang et al 56 Triple conditional knock-outs of SMAD1, SMAD5, and SMAD4 using the Amhr2-cre mouse model results in sterile females due to oviductal malformations, impaired decidualization, and an inability to assemble a closed uterine lumen following implantation Rodriguez et al 57 SMAD2/3 Conditional uterine epithelial SMAD2/3 knock-out using Lactoferrin-iCre mouse model results in endometrial hyperplasia by 12-weeks of age and metastatic tumors by 9 months of age Kriseman et al 146 levels of progesterone, whereas the stromal cells in mice require not only the increase in progesterone signaling, but also the mechanical stimulation of an implanting embryo.…”

“…Subsequent studies have shown that signaling of the BMPs through cell surface receptors, such as ALK2 and ALK3, is critical for inducing decidualization and that their conditional deletion from the uterus using progesterone‐receptor cre (PRcre) leads to infertility, impaired embryo implantation, and defective endometrial decidualization 53,54 . In addition to showing that BMPs exert their signals via a cell surface receptor complex, recent studies have shown that the transcription factors SMAD1 and SMAD5 are required to complete the decidualization process in response to BMPs within the endometrium 55–57 . Hence, BMP signaling, via the ALK2 and ALK3 receptors and the SMAD1/SMAD5 transcription factors, is critical for reprogramming endometrial stroma into functional decidua during early pregnancy.…”