Successful implantation of an embryo is the result of reciprocal interactions between the implantation competent blastocyst and the receptive uterus. An emerging concept is that many of the evolutionary conserved genes, including those encoding Wnts and their receptors are potential players in the process of embryo implantation and spacing in the uterus. Wnt protein has been recently implicated for its association with early embryo development, blastocyst attachment, uterine decidualization and maintenance of uterine embryo orientation and boundaries during pregnancy. However, how the cell fates in the implanting embryo and uterus are specified with the progression of pregnancy remains largely unknown. Better understanding of the signaling mechanism that participates in embryo-uterine interactions during implantation is critical to pregnancy outcome. Wnt proteins bind to and signal through members of the Frizzled family (Fzd) of 7 transmembrane domain receptors. In addition, 2 single-span transmembrane proteins, the low-density lipoprotein receptor-related proteins LRP5 and LRP6, function as Wnt coreceptors. This signaling is regulated by several extracellular antagonists, the secreted Frizzled-related proteins (sFRP) and Dickkopfs (DKKs). We propose that gradients of Wnt-Fzd signaling created by DKK proteins play physiologic roles in coordinating uterine receptivity for implantation, and specifying cell fates during decidualization. This will be tested by conditional inactivation of Wnt signaling by over expression of its extracellular antagonist DKK1and/or DKK3.
Our specific aims are to study in mice: (1) Does the uterus express DKKs 1-4 and LRP5/6during the peri implantation period (days 1-8) and (2) Does conditional inactivation of Wnt function by adenoviral DKK1 expression interfere with embryo implantation and decidualization? We will use molecular and physiological approaches to address these questions. This study is aimed at improving female fertility and developing novel approaches to better contraception. ? ? ?
