The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue\r\ninteractions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and\r\nstromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the\r\nuterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2d/d), the uterine epithelium\r\nexhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine\r\nepithelium and stroma of Msx1/2d/d mice revealed an elevated expression of several members of the Wnt gene family in the\r\npreimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated b-catenin, stimulating the\r\nproduction of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via\r\nthe FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and\r\ncreating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network,\r\ninvolving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymalepithelial\r\ndialogue critical for successful establishment of pregnancy.
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