Abstract
Implantation of a blastocyst in the uterus is a multistep process tightly controlled by an intricate regulatory network of interconnected ovarian, uterine, and embryonic factors. Bone morphogenetic protein (BMP) ligands and receptors are expressed in the uterus of pregnant mice, and BMP2 has been shown to be a key regulator of implantation. In this study, we investigated the roles of the BMP type 1 receptor, activin-like kinase 2 (ALK2), during mouse pregnancy by producing mice carrying a conditional ablation of Alk2 in the uterus (Alk2 cKO mice). In the absence of ALK2, embryos demonstrate delayed invasion into the uterine epithelium and stroma, and upon implantation, stromal cells fail to undergo uterine decidualization, resulting in sterility. Mechanistically, microarray analysis revealed that CCAAT/enhancer-binding protein β (Cebpb) expression is suppressed during decidualization in Alk2 cKO females. These findings and the similar phenotypes of Cebpb cKO and Alk2 cKO mice lead to the hypothesis that BMPs act upstream of CEBPB in the stroma to regulate decidualization. To test this hypothesis, we knocked down ALK2 in human uterine stromal cells (hESC) and discovered that ablation of ALK2 alters hESC decidualization and suppresses CEBPB mRNA and protein levels. Chromatin immunoprecipitation (ChIP) analysis of decidualizing hESC confirmed that BMP signaling proteins, SMAD1/5, directly regulate expression of CEBPB by binding a distinct regulatory sequence in the 3′ UTR of this gene; CEBPB, in turn, regulates the expression of progesterone receptor (PGR). Our work clarifies the conserved mechanisms through which BMPs regulate peri-implantation in rodents and primates and, for the first time, uncovers a linear pathway of BMP signaling through ALK2 to regulate CEBPB and, subsequently, PGR during decidualization.
Highlights
The tunica mucosa of the uterus, called the endometrium, must undergo significant changes to become receptive to implantation of the blastocyst
It is known that the bone morphogenetic protein (BMP) pathways are part of this network, and we investigated how one of the Bone morphogenetic protein (BMP) signaling receptors interacts with other factors in the uterus
We discovered that BMPs act in a linear pathway upstream of two other key regulators of implantation, CEBPB and progesterone receptor (PGR)
Summary
The tunica mucosa of the uterus, called the endometrium, must undergo significant changes to become receptive to implantation of the blastocyst. Stromal cells respond to the invasion of the embryo with a wave of proliferation followed by differentiation; this morphological and functional transformation is called decidualization [1]. These steps are fundamental to the implantation process and are dependent upon the action of ovarian progesterone (P4) signaling through its cognate receptor (reviewed in [2]). The development of the embryo and the cycling of the uterus must be synchronized for implantation to occur This synchrony requires complex cell-specific crosstalk, and many factors have been shown to be involved in implantation, it is still unclear how these factors function and interact. Unraveling the signaling processes regulated by BMPs during embryo implantation is important for the understanding of endometrial health
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