Maternal heparin-binding-EGF deficiency limits pregnancy success in mice

Abstract

An intimate discourse between the blastocyst and uterus is essential for successful implantation. However, the molecular basis of this interaction is not clearly understood. Exploiting genomic Hbegf mutant mice, we show here that maternal deficiency of heparin-binding EGF-like growth factor (HB-EGF) defers on-time implantation, leading to compromised pregnancy outcome. We also demonstrate that amphiregulin, but not epiregulin, partially compensates for the loss of HB-EGF during implantation. In search of the mechanism of this compensation, we found that reduced preimplantation estrogen secretion from ovarian HB-EGF deficiency is a cause of sustained expression of uterine amphiregulin before the initiation of implantation. To explore the significance specifically of uterine HB-EGF in implantation, we examined this event in mice with conditional deletion of uterine HB-EGF and found that this specific loss of HB-EGF in the uterus still defers on-time implantation without altering preimplantation ovarian estrogen secretion. The observation of normal induction of uterine amphiregulin surrounding the blastocyst at the time of attachment in these conditional mutant mice suggests a compensatory role of amphiregulin for uterine loss of HB-EGF, preventing complete failure of pregnancy. Our study provides genetic evidence that HB-EGF is critical for normal implantation. This finding has high clinical relevance, because HB-EGF signaling is known to be important for human implantation.amphiregulin ͉ implantation ͉ uterus ͉ blastocyst

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

“…Several tens of genes were up‐regulated 2 h after the T13 injection (Table 1). Among the genes, we focused on Hbegf and Ptgs2 (encoding COX‐2), because they are responsible for decidualization and knockout of these genes interfered with implantation (Lim et al , 1997; Song et al , 2002; Wang et al , 2004; Xie et al , 2007; Large et al , 2014), as was observed in Lpar3 KO mice (Ye et al , 2005). Both Hbegf and Ptgs2 were transiently induced, peaking at 2–9 h after the T13 injection (Fig 3A).…”

“…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).…”

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

“…Maternal deficiency of HB-EGF displays a compromised pregnancy outcome. 25 Beads carrying HB-EGF were very potent in inducing decidualization and stromal cell polyploidy. 26 We wonder whether HB-EGF is the key intermediary between progesterone and E2F8.…”

“…Since HB-EGF has been shown to be regulated by progesterone during decidualization and tightly related to the polyploidization of decidual cells, 25,26 we assumed that HB-EGF may be involved in mediating the regulation of E2F8 expression in mouse uterus during decidualization. Compared with control group, the stromal cells treated with HB-EGF showed an increased proportion of tetraploid (Fig.…”

Molecular mechanisms of membrane interaction at implantation

“…Paria et al (2001) suggested a more defined role for HB-EGF during implantation, based upon the fact that when transferred to pseudo-pregnant mice, HB-EGF-soaked beads induced implantation-like responses, including the expression of HB-EGF on the luminal epithelium, increased vascular permeability, decidualization, and the expression of a variety of implantation markers. However, blastocysts that were devoid of the HB-EGF gene successfully implanted on the uteri of wild-type mice, calling into question the necessity for HB-EGF expression on the blastocyst surface (Xie et al, 2007). Further investigations are required to elucidate the specific role of HB-EGF expression and binding with regards to implantation.…”