FOXO1 regulates uterine epithelial integrity and progesterone receptor expression critical for embryo implantation

PLoS Genet. 2018 Nov 19;14(11):e1007787. doi: 10.1371/journal.pgen.1007787. eCollection 2018 Nov.


Successful embryo implantation requires a receptive endometrium. Poor uterine receptivity can account for implantation failure in women who experience recurrent pregnancy loss or multiple rounds of unsuccessful in vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivity in vivo. Uterine ablation of Foxo1 using the progesterone receptor Cre (PgrCre) mouse model resulted in infertility due to altered epithelial cell polarity and apoptosis, preventing the embryo from penetrating the luminal epithelium. Analysis of the uterine transcriptome after Foxo1 ablation identified alterations in gene expression for transcripts involved in the activation of cell invasion, molecular transport, apoptosis, β-catenin (CTNNB1) signaling pathway, and an increase in PGR signaling. The increase of PGR signaling was due to PGR expression being retained in the uterine epithelium during the window of receptivity. Constitutive expression of epithelial PGR during this receptive period inhibited expression of FOXO1 in the nucleus of the uterine epithelium. The reciprocal expression of PGR and FOXO1 was conserved in human endometrial samples during the proliferative and secretory phase. This demonstrates that expression of FOXO1 and the loss of PGR during the window of receptivity are interrelated and critical for embryo implantation.

Publication types

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

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cell Polarity / genetics
  • Cell Polarity / physiology
  • Decidua / physiology
  • Embryo Implantation / genetics*
  • Embryo Implantation / physiology*
  • Endometrium / cytology
  • Endometrium / metabolism*
  • Female
  • Forkhead Box Protein O1 / deficiency
  • Forkhead Box Protein O1 / genetics*
  • Forkhead Box Protein O1 / metabolism*
  • Gene Expression Profiling
  • Humans
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Receptors, Progesterone / deficiency
  • Receptors, Progesterone / genetics*
  • Receptors, Progesterone / metabolism*
  • Signal Transduction


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Receptors, Progesterone