|Pabona, John Mark -|
|Zeng, Zhaoyang -|
|Simmen, Frank -|
|Simmen, Rosalia -|
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 24, 2010
Publication Date: June 23, 2010
Citation: Pabona, J., Zeng, Z., Simmen, F.A., Simmen, R.C. 2010. Functional Differentiation of Uterine Stromal Cells Involves Cross-regulation between Bone Morphogenetic Protein 2 and Kruppel-like Factor (KLF) Family Members KLF9 and KLF13. Endocrinology. 151(7):3396-3406. Interpretive Summary: Infertility and early pregnancy loss affect 10-15% of couples of fertility age. A significant underlying cause of these reproductive dysfunctions is the developmental asynchrony between the uterus and the implantation-ready embryo, due to the inability of the inner lining of the uterus to enter the state of receptivity for embryo attachment and subsequent implantation. Our group previously identified a nuclear co-regulator of progesterone action, Krüppel-like Factor (KLF) 9, absence in mice lead to sub-fertility with reduced in number of implanted embryos. Another molecule which is also critical for implantation success in mice is Bone Morphogenetic (BMP) 2. This study showed negative cross-regulation between KLF9 and BMP2 during pre-decidualization, and the role of another KLF member, KLF13 in maintaining progesterone sensitivity in the stromal cells undergoing differentiation. Together, these data suggest that loss of the regulatory network leads to altered uterine receptivity and implantation success.
Technical Abstract: The inability of the uterine epithelium to enter a state of receptivity for the embryo to implant is a significant underlying cause of early pregnancy loss. We previously showed that mice null for the Progesterone Receptor (PGR)-interacting protein Kruppel-like Factor (KLF) 9 are subfertile and exhibit reduced uterine progesterone sensitivity. KLF9 expression is high in pre-decidual stroma, is undetectable in decidua, and is enhanced in uteri of mice with conditional ablation of Bone Morphogenetic Protein 2 (BMP2). Given the individual importance of KLF9 and BMP2 for implantation success, we hypothesized that the establishment of uterine receptivity involves KLF9 and BMP2 functional cross-regulation. To address this, we used early pregnant wildtype and Klf9 null mice and KLF9 siRNA-transfected human endometrial stromal cells (HESC) induced to differentiate under standard conditions. Loss of KLF9 in mice and in HESC enhanced BMP2 expression, while recombinant BMP2 treatment of HESC attenuated KLF9 mRNA levels. IGFBP1 and KLF9-related KLF13 expression were positively associated with BMP2 and inversely associated with KLF9. Prolonged, but not short-term, knockdown of KLF9 in HESC reduced IGFBP1 expression. Mouse uterine Igfbp1 expression was similarly reduced with Klf9 ablation. PGR-A and PGR-B expression were positively associated with KLF9 in pre-decidual HESC but not in decidualizing HESC. KLF13 knockdown attenuated BMP2 and PGR-B and abrogated BMP2-mediated inhibition of KLF9, expression. Results support cross-regulation among BMP2, KLF9 and KLF13 to maintain progesterone sensitivity in stromal cells undergoing differentiation and suggest that loss of this regulatory network compromises establishment of uterine receptivity and implantation success.