|John Mark, Pabona -|
|Simmen, Frank -|
|Simmen, Rosalia -|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: August 11, 2009
Publication Date: N/A
Technical Abstract: Our laboratory has identified a novel progesterone receptor (PGR) co-activator protein, designated Krüppel-like Factor 9 (KLF9), whose absence in mice is associated with subfertility with decreased number of implanting embryos due to altered patterns of proliferation, apoptosis and aberrant P-responsiveness of uterine gene expression. Since Klf9 expression occurs predominantly in the pre-receptive stroma, this suggests a role for KLF9 in stromal-epithelial cross-talk in endometrial receptivity. To dissect the regulatory role of stromal KLF9 for embryo implantation, we used immortalized human endometrial stromal cell line (HESC) treated with cAMP, estradiol, and progesterone (cAME) to mimic stromal progression from a proliferative to a decidualized state. Induction of HESC into a decidualized state with cAME-treatment was accompanied by a progressive decrease in KLF9 protein levels and coincident increase in Bmp2 and Pgr transcript levels. Small interfering RNA-mediated silencing of Klf9 decreased Pgr and increased Bmp2 expression. To test the existence of a negative regulatory loop between Klf9 and Bmp2, recombinant BMP2 was added to HESC for 48 h. BMP2 exposure increased Igfbp1, Prl, Wnt4, and KLF9-related member Klf13 expression, whereas, Klf9 and Pgr were significantly attenuated. In mouse uteri of early pregnancy, there is a premature increase in Bmp2 expression at dpc3.5, and this coincided with an increase in Klf13 transcript. While there is an inverse relationship with that of Klf9, Klf9 null mutants showed dysregulation in the genes during decidualization. KLF9 likely functions as a molecular brake for BMP2 and could be manipulated to advance uterine receptivity in clinical conditions where delayed endometrial maturation leads to unsuccessful outcome.