Uterine Wnt/β-catenin signaling is required for implantation

Abstract

Successful implantation relies on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus. We have examined the role of the Wnt͞␤-catenin signaling pathway during the process of implantation and demonstrate that this pathway is activated during two distinct stages. Wnt͞␤-catenin signaling is first transiently activated in circular smooth muscle forming a banding pattern of activity within the uterus on early day 4. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Our results demonstrate that the Wnt͞␤-catenin signaling pathway plays a central role in coordinating uterus-embryo interactions required for implantation.blastocyst ͉ uterus A crucial event during mammalian embryonic development is the process of implantation, during which the free-living blastocyst attaches to the uterine endometrium. Successful implantation depends on precisely orchestrated and reciprocal signaling between the implanting blastocyst and the receptive uterus (1). For instance, blastocysts can only implant once they have been activated by uterine factor(s) that are regulated by ovarian steroid hormones (2). Conversely, expression of several uterine genes are regulated by a signal(s) emanating from activated blastocysts (3, 4). Multiple signaling pathways have been shown to participate in the implantation process, and several cytokines and growth factors have been shown to be expressed in the uterus at the time of implantation and to play important roles in this process (5). However, there is increasing evidence that members of other families of growth factors implicated in embryogenesis may also participate in the implantation process. It has been demonstrated that members of the hedgehog, bone morphogenetic, and Wnt proteins are expressed in the uterus at the time of implantation (6). However, the precise role of these different growth factor signaling pathways in the implantation process has not been determined. Furthermore, the cell types within the uterus that respond to these growth factors are not known. In this study, we set out to determine the role of the canonical Wnt͞␤-catenin signaling pathway in the implantation process. We demonstrate that this pathway is activated during two distinct stages before implantation. Signaling is transiently detected in circular smooth muscle forming a banding pattern of activity. Subsequently, activation is restricted to the luminal epithelium at the prospective site of implantation. Activation at both sites requires the presence of the blastocyst. Furthermore, we show that inhibition of Wnt͞␤-catenin signaling interferes with the process of implantation. Materials and MethodsMating and Experimental Manipulation of Transgenic Animals. The generation and characterization of the TCF͞Lef-LacZ transgenic mice have been described in ...

Uterine sensing of the embryo

“…Under normal conditions, formation of the primary and secondary decidual zones, at least in part, may be driven by Wnt pathway activity. Nonetheless, the data of Mohamed et al (1) …”

“…Wnt antagonists also may attenuate Wnt responses in the mouse because expression of the soluble form of Wnt receptor, sFRP2, is markedly inhibited in mouse endometrium by estrogen (4). Interestingly, Mohamed et al (1) demonstrate that sFRP-2 effectively inhibited the embryo-dependent decidual reaction. Thus, one role of nidatory estrogen might be to suppress expression of this Wnt antagonist to permit uterine responsiveness to the embryonic Wnt signal.…”

“…In this issue of PNAS, Mohamed et al (1) provide new insight into the molecular mechanism of embryo implantation by identifying the Wnt pathway as part of the system the uterus uses to sense and respond to the relatively tiny embryo during the initial stage of implantation in mice. Ovarian steroids coordinate embryonic development to an attachment-competent state with maturation of the uterus to a receptive state.…”

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

“…Analysis of Wnt reporters showed Wnt signaling activation in the uterine epithelium adjacent to the implanting blastocyst. Luminal injection of Wnt7a medium or coated beads could induce Wnt reporter activation, whereas injection of a Wnt antagonist, Sfrp2 (secreted Frizzled-related protein), significantly reduced implantation efficiency (Mohamed et al 2005). Therefore, Wnt signaling activation in the uterine epithelium, likely induced by the blastocyst, may be functionally important for the implantation process.…”

A sequence of events in the uterus prior to implantation in the mouse

“…Mohamed et al [18] found expression of Wnt signaling in the uterus at 2 stages during early pregnancy. They found at first wnt/β-catenin at around 15:00 h on Day 4 transient activity in circular smooth muscle cells at regularly-spaced intervals corresponding to blastocysts.…”