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 Lifr) and GP130 (encoded by Il6st); 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 Lifr knockout (Lifr eKO) mice and conducted a comprehensive gene expression analysis of the endometrium before implantation. We compared these results with those from uterine epithelium-specific Gp130 knockout (Gp130 eKO) mice. Similarly to Gp130 eKO mice, Lifr 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 Erbb2 and c-Fos 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.