The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy

<div><p>Infertility and adverse gynecological outcomes such as preeclampsia and miscarriage represent significant female reproductive health concerns. The spatiotemporal expression of growth factors indicates that they play an important role in pregnancy. The goal of this study is to define the role of the ERBB family of growth factor receptors in endometrial function. Using conditional ablation in mice and siRNA in primary human endometrial stromal cells, we identified the epidermal growth factor receptor (<i>Egfr</i>) to be critical for endometrial function during early pregnancy. While ablation of <i>Her2</i> or <i>Erbb3</i> led to only a modest reduction in litter size, mice lacking <i>Egfr</i> expression are severely subfertile. Pregnancy demise occurred shortly after blastocyst implantation due to defects in decidualization including decreased proliferation, cell survival, differentiation and target gene expression. To place <i>Egfr</i> in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of <i>Egfr</i>, wingless-related MMTV integration site 4 (<i>Wnt4</i>) or boneless morphogenic protein 2 (<i>Bmp2</i>); revealing that not only are <i>Bmp2</i> and <i>Wnt4</i> key downstream effectors of <i>Egfr</i>, but they also regulate distinct physiological functions. In primary human endometrial stromal cells, marker gene expression, a novel high content image-based approach and phosphokinase array analysis were used to demonstrate that <i>EGFR</i> is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries <i>WNK1</i> and <i>AKT1S1</i>, members identified in the kinase array and previously unreported to play a role in the endometrium, also attenuate decidualization. These results demonstrate that EGFR plays an integral role in establishing the cellular context necessary for successful pregnancy via the activation of intricate signaling and transcriptional networks, thereby providing valuable insight into potential therapeutic targets.</p></div