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

by Yasmin M. Vasquez, Xiaoqiu Wang, Margeaux Wetendorf, Heather L. Franco, Qianxing Mo, Tianyuan Wang, Rainer B. Lanz, Steven L. Young, Bruce A. Lessey, Thomas E. Spencer, John P. Lydon, Francesco J. DeMayo 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 unsuccessfulin vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivityin vivo. Uterine ablation ofFoxo1 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 afterFoxo1 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 F OXO1 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 th...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research