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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abortion, Spontaneous / genetics*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Bone Morphogenetic Protein 2 / genetics
  • Cell Differentiation / genetics
  • Decidua / metabolism
  • Endometriosis / genetics
  • ErbB Receptors / genetics*
  • Female
  • Fertility / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Mice
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Pregnancy
  • Pregnancy Complications / genetics*
  • Protein-Serine-Threonine Kinases / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-3 / genetics
  • Signal Transduction / genetics
  • WNK Lysine-Deficient Protein Kinase 1
  • Wnt4 Protein / genetics

Substances

  • AKT1S1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • Intracellular Signaling Peptides and Proteins
  • Minor Histocompatibility Antigens
  • RNA, Small Interfering
  • Wnt4 Protein
  • Wnt4 protein, mouse
  • EGFR protein, human
  • ErbB Receptors
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human