Demonstrating the Critical Role of Uterine Erbb Signaling in Fertility.

Abstract

The establishment of the appropriate embryo-uterine interactions required for successful implantation and pregnancy require the coordinate actions of growth factors and their receptors. The spatiotemporal expression of Erbb ligands and receptors in the periimplantation uterus and embryo suggests that they play a role in reproduction. Numerous Erbb ligands have overlapping expression patterns in the uterus during pregnancy, and gene ablations of individual Erbb ligands do not show a major uterine phenotype due to compensation by other family members. We have identified EGFR (ERBB1) as being induced during the implantation period and hypothesize that EGFR signaling regulates the ability of the endometrium to support embryo implantation. This hypothesis is being tested in vivo using mouse models and in vitro using primary human endometrial stromal (HES) cell culture and a novel high-throughput microscopy assay. In order to circumvent the embryonic lethality of Egfr-/- mice, conditional ablation of Egfr was achieved by crossing an Egfr floxed (Egfr f/f) mouse with a progesterone receptor cre (PRcre) mouse, resulting in Egfr deletion in all PR positive cells (PRcre/+ Egfr f/f; Egfr d/d). Egfr d/d mice are severely subfertile and exhibit reduced implantation and abnormal embryos. Mutant mice demonstrate an ablation of artificial decidualization including defects in morphology, proliferation, apoptosis, differentiation and gene expression. EGFR is induced during in vitro HES cell decidualization and that the use of EGFR knockdown impedes decidualization. Furthermore, these results have been confirmed using a novel, automated image-based microscopy assay. These results strongly indicate that Erbb signaling plays a critical role in female reproduction. Continuation of ongoing studies determining the mechanism of EGFR action and the role of Erbb2 will provide valuable insight and allow further elucidation of complex pathways and the orchestrated molecular interactions vital to reproductive health. This research was supported by NIH Grant RO1CA077530 (to J.P.L.), by NIH R01HD057873 (to JW.J), and by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U54 HD07495 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research. (platform)