Anterior Gradient Homolog 2 and Its Potential Roles In Ovine Pregnancy

Anterior gradient homolog 2 (AGR2) is a proto-oncogene that encodes a secreted protein with biological roles in cell migration, differentiation, and growth, and is also implicated in epithelial barrier function and integrity. AGR2 is up-regulated in prostate cancer, breast cancer, lung cancer, renal carcinomas and endometrial carcinomas, and it contributes to the survival of cells undergoing physiological stress. We previously reported that AGR2 expression in the ovine endometrium increased between days 9 and 12 post-mating, was stimulated by progesterone, and associated with conceptus elongation. In situ hybridization studies localized AGR2 mRNA to the luminal epithelium (LE) of the ovine endometrium. Further, AGR2 mRNA expression is greater from Days 14 to 16 of pregnancy than in the cycle, suggesting a role for conceptus-derived products in regulation of AGR2 expression in the endometrium. Using osmotic pumps to infuse pregnancy levels of hormones into the uterus of cyclic ewes, we found that interferon tau (IFNT) along with cortisol and prostaglandins (PGE2, PGF2α, and PGI2) or both cortisol and prostaglandins increased (P<0.05) expression of AGR2 mRNA in the endometrium compared to controls receiving vehicle and ewes receiving IFNT, cortisol, or prostaglandins alone. A role for AGR2 in placental function during later pregnancy has not been described for any species. Using a model of maternal nutrient restriction, we utilized natural population variance in fetal growth to identify novel genes associated with the development of either intrauterine growth restricted (IUGR) or non-IUGR pregnancies in sheep. Interestingly, microarray analysis of placentomes from IUGR and non-IUGR pregnancies at Day 125 of pregnancy found AGR2 was up-regulated (P