Expression and estradiol regulation of Wnt genes in the mouse blastocyst identify a candidate pathway for embryo-maternal signaling at implantation.

Implantation of mammalian embryos depends on differentiation of the blastocyst to a competent state and of the uterine endometrium to a receptive state. Communication between the blastocyst and uterus ensures that these changes are temporally coordinated. Although considerable evidence indicates that the blastocyst induces expression of numerous genes in uterine tissue, potential signaling mechanisms have yet to be identified. Moreover, whereas a surge of maternal estradiol occurring on Day 4 of pregnancy in the mouse is critically required for many of the peri-implantation uterine changes, whether this surge also affects blastocyst gene expression has not been established. We show here that mouse morulae express genes encoding several members of the Wnt family of signaling molecules. Additional Wnt genes are newly expressed following development to blastocyst. Unexpectedly, Wnt5a and Wnt11 are expressed in embryos that undergo the morula-to-blastocyst transition in vivo, but only weakly or not at all in embryos that do so in vitro. Upregulation of Wnt11 is temporally coordinated with the surge of maternal estradiol on Day 4. Wnt11 fails to be upregulated in blastocysts obtained from mice ovariectomized early on Day 4 or from mice treated with the estradiol antagonist, ICI 182,780. Administration of estradiol-17beta or its metabolite, 4-OH-estradiol, to ovariectomized mice restores Wnt11 expression. Moreover, Wnt11 expression is not upregulated when blastocysts are trapped in the oviduct following ligation of the utero-tubal junction, nor when estradiol-17beta or 4-OH-estradiol are administered to blastocysts in vitro. These results establish a comprehensive profile of Wnt gene expression during late preimplantation development, demonstrate that estradiol regulates gene expression in the blastocyst via uterine factors, and identify Wnts as potential mediators of embryo-uterine communication during implantation.