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

• Published in: PLoS genetics Vol. 10; no. 6; p. e1004451
• Main Authors: Large, Michael J., Wetendorf, Margeaux, Lanz, Rainer B., Hartig, Sean M., Creighton, Chad J., Mancini, Michael A., Kovanci, Ertug, Lee, Kuo-Fen, Threadgill, David W., Lydon, John P., Jeong, Jae-Wook, DeMayo, Francesco J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2014; Public Library of Science (PLoS)
• Subjects: Ablation (Surgery); Abortion, Spontaneous - genetics; Adaptor Proteins, Signal Transducing - genetics; Analysis; Animals; Biology and life sciences; Bone Morphogenetic Protein 2 - genetics; Bone morphogenetic proteins; Cell differentiation; Cell Differentiation - genetics; Decidua - metabolism; Endometriosis - genetics; Epidermal growth factor; ErbB Receptors - genetics; Female; Fertility - genetics; Gene expression; Health aspects; Humans; Infertility; Intracellular Signaling Peptides and Proteins - genetics; Kinases; Medicine and Health Sciences; Mice; Mice, Knockout; Minor Histocompatibility Antigens; Physiological aspects; Pregnancy; Pregnancy Complications - genetics; Protein-Serine-Threonine Kinases - genetics; Receptor, ErbB-2 - genetics; Receptor, ErbB-3 - genetics; RNA Interference; RNA, Small Interfering; Signal Transduction - genetics; WNK Lysine-Deficient Protein Kinase 1; Wnt4 Protein - genetics; Women; Womens health; Texas
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004451

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 (Egfr) to be critical for endometrial function during early pregnancy. While ablation of Her2 or Erbb3 led to only a modest reduction in litter size, mice lacking Egfr 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 Egfr in a genetic regulatory hierarchy, transcriptome analyses was used to compare the gene signatures from mice with conditional ablation of Egfr, wingless-related MMTV integration site 4 (Wnt4) or boneless morphogenic protein 2 (Bmp2); revealing that not only are Bmp2 and Wnt4 key downstream effectors of Egfr, 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 EGFR is a critical regulator of human decidualization. Furthermore, inhibition of EGFR signaling intermediaries WNK1 and AKT1S1, 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.