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United States Department of Agriculture

Agricultural Research Service

Research Project: IMPACT OF EARLY DIETARY FACTORS ON CHILD DEVELOPMENT AND HEALTH Title: Wnt antagonist DKK1 is a target of Kruppel-like factor 9 (KLF9) in endometrial stromal cells: Implications for uterine receptivity

Authors
item Pabona, John Mark -
item Simmen, Frank -
item Nikiforov, Mikhail -
item Dazhong, Zhuang -
item Giudice, Linda -
item Simmen, Rosalia -

Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: March 15, 2010
Publication Date: June 28, 2010
Citation: Pabona, J.P., Simmen, F.A., Nikiforov, M.A., Dazhong, Z., Giudice, L., Simmen, R.C. 2010. Wnt antagonist DKK1 is a target of Kruppel-like factor 9 (KLF9) in endometrial stromal cells: Implications for uterine receptivity [abstract]. Endocrine Reviews. 31(3)Supplement 1:S2077.

Technical Abstract: A significant underlying cause of pregnancy loss in mammals is the inability of the uterine epithelium to enter a "state of receptivity" for embryo implantation, due partly to the dysfunctional response of endometrial cells to progesterone (P). We previously showed that mice null for the Sp1-related transcription factor KLF9 exhibit reduced numbers of implantation sites and display aberrant uterine growth-proliferative response and partial P resistance. We also showed that KLF9 regulates the expression and activity of the progesterone receptor (PR) in vivo and in vitro. To examine the contribution of KLF9 to P-responsive transcriptional programs in stromal cells for luminal epithelial receptivity, the human endometrial stromal cell line HESC was treated with a differentiation cocktail to mimic the peri-implantation hormonal environment, and in the presence of scrambled (control) or KLF9 siRNAs were analyzed by gene microarray. A number of Wnt signaling pathway components including the Wnt antagonist DKK1 were identified as KLF9-regulated. The association between KLF9 and DKK1 was evaluated in HESC and in uteri of early pregnant WT and Klf9 null mice. Time-course kinetics showed a parallel decrease in KLF9 protein and DKK1 transcript levels in decidualizing (HESC) stroma. Dkk1 expression in whole uteri was highest at day post-coitum (dpc) 3.5 relative to dpc 2.5 and 4.5 (vaginal plug=dpc0.5). However, uterine Dkk1 expression was significantly attenuated at dpc3.5 with Klf9 null mutation. In eutopic endometrium of women without endometriosis, highest levels of KLF9 and DKK1 transcripts were demonstrated at the mid-secretory phase, relative to the other menstrual cycle phases. In women with endometriosis, KLF9 and DKK1 expression in eutopic endometrium was coordinately reduced at the mid-secretory phase. HESC co-transfected with the human DKK1 promoter/5'regulatory region (-2238 to +112 nt) linked to a Luciferase gene-reporter and control or KLF9 siRNAs had significantly lower (greater than 50%) DKK1 promoter activity with KLF9 knockdown, compared to control siRNA-treated cells. Given that DKK1 is a P/PR-regulated gene and that appropriate Wnt signaling is critical for uterine receptivity, our studies demonstrating DKK1 as a potential KLF9 target in stromal cells provide a novel mechanism by which the KLF/PR transcriptional network may transduce P-regulated paracrine signal(s) to neighboring epithelial cells, for successful embryo implantation.

Last Modified: 10/23/2014
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