AMPHIREGULIN IS AN IMPLANTATION-SPECIFIC AND PROGESTERONE-REGULATED GENE IN THE MOUSE UTERUS

A synchrony between the activated state of the blastocyst and differen tiation of the uterus to the receptive state is essential to the proce ss of implantation. This process is directed by progesterone (P4) and estrogen. The mechanism by which P4 differentiates the uterus, enablin g estrogen to initiate implantation, is unknown but likely to involve localized induction of growth and differentiation factors. We have clo ned the murine amphiregulin (AR) gene, a newly discovered member of th e: epidermal growth factor family, and demonstrate that its expression is implantation-specific and P4-regulated in the mouse uterus. A tran sient surge in AR mRNA levels occurred throughout the uterine epitheli um on day 4 of pregnancy. With the onset of blastocyst attachment late on day 4, AR mRNA accumulated in the luminal epithelium exclusively a t the sites of blastocysts. Thus, AR expression correlated first with rising P4 levels and then with the attachment reaction. The rapid indu ction of AR mRNA in the ovariectomized uterus only by P4 and abrogatio n of this induction by RU-486 (a P4 receptor antagonist) suggest that this uterine gene is regulated by P4. AR appeared to exhibit preferent ial phosphorylation of epidermal growth factor receptor in the uterus over that in the blastocyst. This is a first report of a P4-regulated uterine epithelial cell growth factor that is associated with epitheli al cell differentiation during implantation. The association of AR in implantation is further documented by its down-regulation in the day 4 pregnant uterus in which uterine receptivity and implantation were di srupted by estrogen or RU-486 treatment on day 3. These results furthe r indicate that the expression of the AR gene could serve as a molecul ar marker for the receptive state of the uterus for implantation.