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PHENOTYPIC ANALYSIS OF MICE LACKING PROGESTERONE RECEPTOR B ISOFORM.
Mulac-Jericevic, Biserka1, Mullinax, Robert1, Conneely, Orla1, 1
ABSTRACT- Progesterone regulates reproductive function by interaction with two intracellular receptors, PR-A and PR-B, that arise from a single gene. To establish the selective physiological roles of PR isoforms in vivo, we have selectively ablated PR-A (PRAKO) or PR-B (PRBKO) expression in mice. Ablation of PR-A results in severe abnormalities in ovarian and uterine function but does not affect responses of the mammary gland or thymus to progesterone. Analysis of uterine function of PRAKO mice reveals an unexpected progesterone-dependent proliferative activity of PR-B in the epithelium and provides evidence that the tissue specific functions of this isoform are due to specificity of target gene transactivation rather than differences in spatiotemporal expression relative to PR A. Contrary to PRAKO mice, PRBKO mice are fertile and have successful pregnancies that result in normal litter sizes and Mendelian distribution. Histological studies of uteri isolated from PRBKO mice revealed normal sensitivity to estrogen and progesterone. Specifically, progesterone acting through PR-A alone antagonizes estrogen-induced proliferation of the uterine epithelium in PRBKO mice. Furthermore, PRBKO mice display normal thymic involution when treated with estrogen and progesterone. However, analysis of the morphogenic responses of the mammary gland in these mice to estrogen and progesterone showed significantly reduced ductal branching that was associated with a decrease in ductal proliferation. Our results indicate that the differential transaction activities of both isoforms observed in vitro are associated with a differential contribution of each isoform to the tissue specific reproductive functions of progesterone.
KEY WORDS: Progesterone
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