Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors

Abstract

The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone morphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgehog (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Despite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling proteins. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IGF-1), but not other proteins, induce many of the same discrete local responses elicited by the blastocyst, including increased localized vascular permeability, decidualization, and expression of Bmp2 at the sites of the beads. By contrast, the expression domains of Indian hedgehog (Ihh), patched, and noggin become restricted as decidualization proceeds. Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads.

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 signaling required for proper decidualization is generated through two types of cell–cell interactions, i.e., embryo‐epithelial and epithelial–stromal interactions. 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).…”

“…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). …”

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

“…For the pregnant ones, the uteri and placentas (if have) were collected at 1300-1400 h on gestational days 1, 2, 3, 4, 13, 20 and one day after delivery, respectively. On gestational day 4 when implantation just occurred, the uteri were collected as the implantation sites and the inter-implantation sites after venous injection of Evans blue dye (1% in saline) at 2200-2300 h [17]. Another forty mice were subjected to ovariectomies, and two weeks later, the mice were randomly divided into four groups.…”

Bone morphogenetic protein expression in newborn rat kidneys after prenatal exposure to radiofrequency radiation

“…BMP-2 is involved in blastocyst implantation and cavity formation during gastrulation [Coucouvanis and Martin, 1999;Paria et al, 2001]. BMP-4 heterozygous null mutant mice exhibit abnormalities in the kidney/ureter morphogenesis, including among others, hypo/dysplasia of the kidneys, hydroureters etc.…”