LIFR-Mediated ERBB2 Signaling Is Essential for Successful Embryo Implantation in Mice

In eutherian mammals, embryo implantation is a critical process for a successful pregnancy. In mice, the activation of the leukemia inhibitory factor (LIF) receptor-STAT3 signaling axis induces embryo adhesion and decidualization. The LIF receptor is believed to function as a heterodimer composed of LIFR (encoded by <i>Lifr</i>) and GP130 (encoded by <i>Il6st</i>); however, their distinct expression patterns in the uterine epithelium immediately prior to implantation suggest divergent functional roles. In this study, we generated uterine epithelium-specific <i>Lifr</i> knockout (<i>Lifr</i> eKO) mice and conducted a comprehensive gene expression analysis of the endometrium before implantation. We compared these results with those from uterine epithelium-specific <i>Gp130</i> knockout (<i>Gp130</i> eKO) mice. Similarly to <i>Gp130</i> eKO mice, <i>Lifr</i> eKO mice were completely infertile. We identified 299 genes with expression changes greater than twofold following gene deletion; among these, 31 genes were downregulated and 57 genes were upregulated in both eKO models. Many of the downregulated genes were previously implicated in uterine function. Hub gene analysis identified <i>Erbb2</i> and <i>c-Fos</i> as key regulators in both models. Further experiments using an ERBB2 inhibitor suggested that LIFR-ERBB2-mediated signaling plays a crucial role in embryo implantation.