REPRODUCTIVE PHENOTYPES OF THE PROGESTERONE-RECEPTOR NULL MUTANT MOUSE

Although progesterone has been traditionally associated with the estab lishment and maintenance of mammalian pregnancy, a number of studies h ave implicated physiological roles for this steroid hormone in other r eproductive events. At present most of the downstream molecular and ce llular mechanisms by which progesterone exerts its effects are unclear ; however, the progesterone signal is known to be mediated initially b y the progesterone receptor (PR), a member of the nuclear receptor sup erfamily of transcription factors. In most tissues studied, the PR is induced by ovarian estrogen via the estrogen receptor (ER), thereby im plying that many of the observed reproductive physiological responses attributed to PR could conceivably be due to the combined effects of p rogesterone and estrogen. Therefore, to define clearly the distinct ro les of progesterone and estrogen in vivo and to understand better prog esterone function in a physiological context, we recently have generat ed a novel mouse strain in which both forms of the PR were ablated usi ng gene targeting/embryonic stem cell techniques. Surprisingly, both m ale and female embryos, homozygous for the PR null mutation, developed to adulthood at the normal Mendelian frequency with no deviation in t he sex ratio. Although developmental defects have yet to be detected i n the adult male PR homozygote, extensive reproductive abnormalities w ere observed in the female. The reproductive phenotypes consisted of a n inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development and an impairment in the induction of a sexual behavioral response. Collectively, these results provide d irect in vivo evidence for progesterone's role as a pleiotropic coordi nator of diverse reproductive events that together ensure female ferti lity. Finally, we believe that this animal model will be an invaluable tool in exploring the effects of progesterone in physiological system s other than reproduction and may, in the future, help to redefine pro gesterone not just as a sex steroid hormone but also as a key regulato r of diverse physiological processes.