Abdominal B (AbdB) Hoxa genes: Regulation in adult uterus by estrogen and progesterone and repression in Mullerian duct by the synthetic estrogen diethylstilbestrol (DES)

Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri- implantation period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. These observations, combined with the stringent regulation of uterine implantation by ovarian steroids, prompted us to test whether estrogen and progesterone directly regulate the expression of Hoxa- 10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activation is blocked by the progesterone receptor antagonist RU486 and is independent of new protein synthesis. In addition, Hoxa-10 expression is repressed by estrogen in a protein synthesis-independent manner. Analysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are also activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of AbdB Hox gene expression in the adult uterus by ovarian steroids is a property related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We next examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors. Previous work has demonstrated that perinatal administration of the synthetic estrogen diethylstilbestrol (DES) to mice and humans produces uterine, cervical, and oviductal malformations. Certain of these phenotypes resemble those in Hoxa-10 knockout mice, suggesting that Hoxa-10 gene expression might be repressed by DES during reproductive tract morphogenesis. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, represses the expression of Hoxa-10 in the Mullerian duct. Thus, these data not only establish a direct link between ovarian steroids and AbdB Hoxa gene expression in the adult uterus, but also provide a potential mechanism for the teratogenic effects of DES on the developing reproductive tract.