(P-146) SMRT Plays an Important Role for Implantation and Decidualization.

Abstract Authors: Dinh Nam Tran¹, Loan Thi Kim Nguyen¹, Ronald N. Cohen², Tae Hoon Kim¹, and Jae-Wook Jeong<sup>1



1</sup>Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO.

²Department of Medicine, The University of Chicago, Chicago, IL

Abstract Text: Infertility is a major health issue that affects an estimated 10–15% of couples worldwide and has been growing at an alarming rate. Over 75% of failed pregnancies involve implantation defects. Epigenetic regulation has indeed gained significant attention for its role in implantation and decidualization during early pregnancy. However, little is known about the role of epigenetic regulation that contributes to early pregnancy establishment. Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) is a transcriptional co-regulator of a variety of nuclear receptors and transcription factors. Our immunohistochemical analysis revealed that the expression of SMRT was significantly decreased in endometrial epithelial and stromal cells from infertile women with endometriosis compared to controls. Since mouse embryos with homozygous deletion of SMRT are embryonically lethal, we generated a mouse model with Smrt conditionally ablated in Pgr-positive cells (Pgr^cre/+Smrt^f/f; Smrt^KO) to determine the effect of SMRT loss in the uterus. Ablation of Smrt in the uterus was confirmed by RT-qPCR, Western blot and IHC analyses. In fertility tests of female Smrt^f/f and Smrt^KO mice over 6 months, Smrt^f/f mice were fertile, whereas Smrt^KO mice were sterile. The number of implantation sites at GD4.5 revealed normal in both Smrt^f/f and Smrt^KO mice and histological analysis indicated normal embryo attachment to the uterine horn in Smrt^f/f and Smrt^KO mice. However, we did not detect implantation sites in the uterine horns of Smrt^KO mice at GD5.5. Our histological analysis indicated that uterine luminal epithelial cells in Smrt^f/f mice were disappeared, and embryos were attached to the uterine horn and surrounded by decidualized cells. However, in Smrt^KO mice, uterine luminal epithelial cells were intact, and decidual cells were not evident. These results suggest that Smrt^KO mice were infertile due to defective embryo implantation. We then used an artificial decidualization model to examine how Smrt ablation affects decidualization. Smrt^f/f mice displayed a decidual uterine horn that responded well to this decidual induction. However, Smrt^KO mice had a significant defect in the decidual response. We confirmed this decidual defect by histological analysis and reduced expression of the decidualization markers Bmp2 and Wnt4 in the Smrt^KO mouse uterus. These results demonstrate that Smrt^KO mice were infertile due to a decidualization defect. This work was supported by NIH P01HD106485 and R01HD102170.