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 red uced fertility due to defects in implantation. During the peri-implant ation period Hoxa-10 is sequentially expressed in the uterine epitheli um and stroma. These observations, combined with the stringent regulat ion of uterine implantation by ovarian steroids, prompted us to test w hether estrogen and progesterone directly regulate the expression of H oxa-10 and other AbdB Hoxa genes. Here we show that Hoxa-10 expression in the adult uterus is strongly activated by progesterone. This activ ation 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. An alysis of adjacent AbdB Hoxa genes reveals that Hoxa-9 and a-11 are al so activated in a colinear fashion by progesterone but differentially regulated by estrogen. These results suggest that the regulation of Ab dB Hox gene expression in the adult uterus by ovarian steroids is a pr operty related to position within the cluster, mediated by the direct action of estrogen and progesterone receptors upon these genes. We nex t examined whether the embryonic expression of Hoxa10 is regulable by hormonal factors, previous work has demonstrated that perinatal admini stration of the synthetic estrogen diethylstilbestrol (DES) to mice an d humans produces uterine, cervical, and oviductal malformations. Cert ain of these phenotypes resemble those in Hoxa-10 knockout mice, sugge sting that Hoxa-10 gene expression might be repressed by DES during re productive tract morphogenesis. Exposure of the developing female repr oductive tract to DES, either in vivo or in organ culture, represses t he expression of Hoxa-10 in the Mullerian duct. Thus, these data not o nly establish a direct link between ovarian steroids and AbdB Hoxa gen e expression in the adult uterus, but also provide a potential mechani sm for the teratogenic effects of DES on the developing reproductive t ract. (C) 1998 Academic Press.