Bmp2 Is Critical for the Murine Uterine Decidual Response

Abstract

The process of implantation, necessary for all viviparous birth, consists of tightly regulated events, including apposition of the blastocyst, attachment to the uterine lumen, and differentiation of the uterine stroma. In rodents and primates the uterine stroma undergoes a process called decidualization. Decidualization, the process by which the uterine endometrial stroma proliferates and differentiates into large epithelioid decidual cells, is critical to the establishment of fetal-maternal communication and the progression of implantation. The role of bone morphogenetic protein 2 (Bmp2) in regulating the transformation of the uterine stroma during embryo implantation in the mouse was investigated by the conditional ablation of Bmp2 in the uterus using the (PR-cre) mouse. In rodents and primates the process of implantation consists of attachment and invasion of the uterine luminal epithelium. Successful embryo implantation in these species requires the rapid remodeling of the uterine stromal cells in a process termed decidualization (as reviewed previously [30]). Decidualization is a process characterized by morphological and functional changes in the uterine stromal cells that is characterized by endometrial stroma proliferation and differentiation into large epithelioid decidual cells. This process is critical for establishment of a fetal-maternal interface during implantation. Although the expression of many genes, including steroid hormone receptors, cytokines, growth factors, and several developmental factors, has been implicated in this process, direct in vivo evidence of gene function has been limited. This is largely due to the fact that the ablation of many of the genes implicated in this process result in early lethality or other developmental consequences that preclude further study. Here we investigate the role of a member of the bone morphogenetic protein family, Bmp2, in the process of embryo implantation.Bone morphogenetic proteins (Bmps) are multifunctional growth factors that belong to the transforming growth factor ␤ (TGF-␤) superfamily. The roles of Bmps in embryonic development and cellular functions in postnatal and adult animals have been extensively studied in recent years. The activity of Bmp growth factors was first described in the induction of bone formation (56). Bmp2 was identified later as a soluble factor capable of inducing ectopic cartilage and bone formation in vivo when implanted into muscular tissues (58, 61). Numerous studies have characterized the role of Bmp2 as an essential osteoblast and osteoclast differentiation factor (reviewed in reference 5). Mice with a targeted deletion of Bmp2 are embryonic lethal due to a failure of proamniotic canal closure in the majority of mice or abnormal cardiac development in the surviving mice (67). In the uterus of pregnant mice, Bmp2 expression is absent in the preimplantation period and during implantation is initially detected in the stroma surrounding the site of blastocyst attachment. As implantation progresses, expression of Bmp2 ...

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…We also found that downstream of LPA 3 , Bmp2/Wnt4 signaling (Table 2 and Fig 4A) was activated. Bmp2 and Wnt4 are well‐known decidual factors acting downstream of HB‐EGF signaling (Paria et al , 2001; Lee et al , 2007; Franco et al , 2011; Li et al , 2013; Large et al , 2014). Interestingly, a significant negative correlation of gene expression profiles was observed between T13‐injected uteri and uteri null for either Egfr (a target of HB‐EGF), Bmp2, and Wnt4 (Large et al , 2014; Fig 4B).…”

“…The raw data of uterine‐specific Egfr or Wnt4 KO were kindly disclosed by the corresponding author of the previous article (Large et al , 2014). The data of Bmp2 (Lee et al , 2007; accession no. GSE10193), Egfr, or Wnt4 KO were analyzed using R (https://www.R-project.org/).…”

“…Maternal factors such as heparin‐binding epidermal growth factor (HB‐EGF) and cyclooxygenase‐2 (COX‐2) are induced in the epithelium surrounding the embryos (embryo‐epithelial interaction) and then act on the stroma to induce the expression of bone morphogenic protein 2 (Bmp2) and wingless‐related MMTV integration site 4 (Wnt4) in stroma (epithelial–stromal interaction; Lim et al , 1997; Paria et al , 2001; Song et al , 2002; Wang et al , 2004; Xie et al , 2007; Large et al , 2014). Mice in which these maternal factors (HB‐EGF, COX‐2, Bmp2, and Wnt4) are knocked out showed obvious defects in decidual reactions (Lim et al , 1997; Wang et al , 2004; Lee et al , 2007; Xie et al , 2007; Franco et al , 2011; Li et al , 2013; Large et al , 2014). Based on these observations, it has been proposed that some factor(s) are present in the embryo‐epithelial boundary and induce the expression of HB‐EGF and COX‐2 in the epithelium, which in turn facilitate the following decidual reactions through up‐regulation of Bmp2 and Wnt4 (Paria et al , 2001; Cha et al , 2012).…”

Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

“…In stark contrast, the stimulated horn of the uterine GR KO mice showed no significant increase in uterine size compared with the unstimulated horn. Previous studies have determined molecular markers of decidualization, including induction of the genes bone morphogenetic protein 2 (Bmp2) and wingless-related MMTV integration site 4 (Wnt4) (10,11). The expression of Bmp2 and Wnt4 mRNA was highly induced in the decidual horn of the control mice (Fig.…”

The role of Wnt signaling members in the uterus and embryo during pre-implantation and implantation

“…Thus, the expressions of BMP2 and Wnt4, which were induced during stromal decidualization in the mouse, were conserved in the human stromal cells undergoing decidualization [52]. Studies reveal that Wnt4 is not the only Wnt ligand that is associated with BMP2, since BMP2 was shown to be responsible for the upregulation of Wnt6 of murines [53]. Wnt6 was shown to be expressed in proliferating stromal cells of mice during post-implantation uterine development.…”