Reproductive functions of the progesterone receptor isoforms: lessons fromknock-out mice

Progesterone plays a central coordinate role in diverse reproductive events associated with establishment and maintenance of pregnancy. In humans and other vertebrates. the biological activities of progesterone are mediated b y two proteins, A (PR-A) and B (PR-B) that arise from the same gene and fun ction as progesterone activated transcription factors that exhibit differen t transcription regulatory activities in vitro. Mice lacking both PR isofor ms (PRKO mice) exhibit pleiotropic reproductive abnormalities. To address t he physiological role of the individual isoforms, we have selectively ablat ed PR-A expression in mice (PRAKO). We have demonstrated that PR-B mediates a subset of the reproductive functions of P. Ablation of PR-A does not aff ect responses of the mammary gland or thymus to P but results in severe abn ormalities in ovarian and uterine function. Analysis of urine function of P RAKP mice reveals an unexpected P-dependent proliferative activity of PR-B in the epithelium and provides evidence that the tissue-specific reproducti ve effects of this isoform are due to specificity of target gene transactiv ation rather than differences in tissue-specific expression relative to PR- A. Taken together, our data indicate that PR-A and PR-B act in vivo as two functionally distinct transcription factors, (C) 2001 Elsevier Science Irel and Ltd. All rights reserved.