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PLoS Genet. 2014 Jun 19;10(6):e1004451. doi: 10.1371/journal.pgen.1004451. eCollection 2014 Jun.

The epidermal growth factor receptor critically regulates endometrial function during early pregnancy.

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
2
Dan L. Duncan Cancer Center Division of Biostatistics, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
3
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
4
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California, United States of America.
5
Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas, United States of America.
6
Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, Michigan, United States of America.

Abstract

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.

PMID:
24945252
PMCID:
PMC4063709
DOI:
10.1371/journal.pgen.1004451
[Indexed for MEDLINE]
Free PMC Article
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