Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities (original) (raw)
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Reproductive tissue selective actions of progesterone receptors
Reproduction, 2004
The steroid hormone, progesterone, plays a central coordinate role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PR-A and PR-B. These receptors arise from the same gene and exhibit both overlapping and distinct transcriptional activitiesin vitro. To delineate the individual roles of PR-A and PR-Bin vivo, we have generated mouse models in which expression of a single PR isoform has been ablated. Analysis of the reproductive phenotypes of these mice has indicated that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive responses to progesterone. While selective ablation of the PR-A protein (PR-A knockout mice, PRAKO mice) shows normal mammary gland response to progesterone but severe uterine hyperplasia and ovarian abnormalities, ablation of PR-B protein (PRBKO mice) does not affect biologica...
Reproductive functions of progesterone receptors
Recent progress in …, 2002
The steroid hormone progesterone plays a central role in the reproductive events associated with pregnancy establishment and maintenance. Physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed as two protein isoforms, PR-A and PR-B. Both proteins arise from the same gene and are members of the nuclear receptor superfamily of transcription factors. Since these two isoforms were identified in the early 1970s, extensive controversy has existed regarding the selective contributions of the individual PR proteins to the physiological functions of progesterone. During the past decade, significant progress has been made in this regard using two complimentary approaches. First, analysis of the structural and functional relationships of each isoform using in vitro systems has generated compelling evidence to support the conclusion that PR-A and PR-B have different transcription activation properties when liganded to progesterone. Second, the advent of gene-targeting approaches to introduce subtle mutations into the mouse genome has facilitated the evaluation of the significance of observations made in vitro in a physiological context. Selective ablation of PR-A and PR-B proteins in mice using these technologies has allowed us to address the spatiotemporal expression and contribution of the individual PR isoforms to the pleiotropic reproductive activities of progesterone. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided proof of concept that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are, indeed, reflected in an ability of the individual isoforms to elicit distinct, physiological responses to progesterone. In PR-A knockout mice, in which the expression of the PR-A isoform is selectively ablated (PRAKO), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect responses of the mammary gland or thymus to progesterone but instead results in severe abnormalities in ovarian and uterine function, leading to female infertility. These tissue-selective activities of PR-B are due to this isoform's ability to regulate a subset of progesterone-responsive target genes in reproductive tissues rather than to differences in its spatiotemporal expression relative to the PR-A isoform. More recent studies using PR-B knockout (PRBKO) mice have shown that ablation of PR-B does not affect ovarian, uterine, or thymic responses to progesterone but rather results in reduced mammary ductal morphogenesis. Thus, PR-A is both necessary and sufficient to elicit the progesterone-dependent reproductive responses necessary for female fertility, while PR-B is required to elicit normal proliferative responses of the mammary gland to progesterone. This chapter will summarize recent progress in our understanding of the selective contribution of the two PR isoforms to progesterone action.
Steroids, 2003
The steroid hormone, progesterone, is a central coordinator of all aspects of female reproductive activity. The physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed from a single gene as two protein isoforms and that are members of the nuclear receptor superfamily of transcription factors. Analysis of the structural and functional relationships of each isoform using in vitro systems has demonstrated that the PR-A and PR-B proteins have different transcription activation properties when liganded to progesterone. More recently, selective ablation of the PR-A and PR-B proteins in mice had facilitated examination of the contribution of the individual PR isoforms to the pleiotropic reproductive activities of progesterone. Analysis of the phenotypic consequences of these mutations on female reproductive function has provided proof of concept that the distinct transcriptional responses to PR-A and PR-B observed in cell-based transactivation assays are reflected in a distinct tissue-selective contribution of the individual isoforms to the reproductive activities of progesterone. In PR-A knockout mice, in which the expression of the PR-A isoform is selectively ablated (PRAKO), the PR-B isoform functions in a tissue-specific manner to mediate a subset of the reproductive functions of PRs. Ablation of PR-A does not affect response of the mammary gland or thymus to progesterone but results in severe abnormalities in ovarian and uterine function leading to female infertility. More recent studies using PR-B knockout (PRBKO) mice have shown that ablation of PR-B does not affect either ovarian, uterine or thymic responses to progesterone but results in reduced mammary ductal morphogenesis and alveologenesis during pregnancy. Thus, PR-A is both necessary and sufficient to elicit the progesterone-dependent reproductive responses necessary for female fertility, while the PR-B isoform is required to elicit normal proliferative and differentiative responses of the mammary gland to progesterone. This review will summarize our current understanding of the selective contribution of the two PR isoforms to progesterone action.
Reproductive functions of the progesterone receptor
2000
The steroid hormone progesterone plays a central role in the reproductive events associated with pregnancy establishment and maintenance. Physiological effects of progesterone are mediated by interaction of the hormone with specific intracellular progesterone receptors (PRs) that are expressed as two protein isoforms, PR-A and PR-B. Both proteins arise from the same gene and are members of the nuclear receptor superfamily of transcription factors. Since these two isoforms were identified in the early 1970s, extensive controversy has existed regarding the selective contributions of the individual PR proteins to the physiological functions of progesterone. During the past decade, significant progress has been made in this regard using two complimentary approaches. First, analysis of the structural and functional relationships of each isoform using in vitro systems has generated compelling evidence to support the conclusion that PR-A and PR-B have different transcription activation pro...
Endocrine Defects in Mice Carrying a Null Mutation for the Progesterone Receptor Gene*
Endocrinology, 1997
Mice carrying a null mutation of the progesterone receptor gene exhibit several reproductive abnormalities, including anovulation, attenuated lordotic behavior, uterine hyperplasia, and lack of mammary gland development. The hormonal correlates of these abnormalities are unknown, however, and were the focus of these studies. Serum samples from female wild-type (WT) and progesterone receptor knockout (PRKO) mice were obtained and analyzed by RIA for LH, FSH, PRL, estrogen (E 2), and progesterone. Hypothalamic tissues were also processed for measurement of LHRH by RIA. Serum LH levels in PRKO mice were found to be elevated by approximately 2-fold over basal (metestrus) values in WT mice. By contrast, basal FSH levels were not different in PRKO and WT mice. Basal levels of E 2 and progesterone in serum were likewise similar in the two groups, as were hypothalamic LHRH concentrations. Basal PRL levels were slightly higher in PRKO vs. WT mice. Ovariectomy of both groups of mice was accompanied by significant increases in both LH and FSH.
Proceedings of the National Academy of Sciences, 1999
Estrogen is known to increase progesterone receptor (PR) levels in the wild-type mouse uterus, and this estrogen induction was thought to be important for progesterone action through the PR. The estrogen receptor ␣ knockout (ERKO) mouse uterus was observed to express PR mRNA that cannot be induced by estrogen. Progesterone action was characterized to determine whether it was diminished in ERKO mice. The PR protein is present in the ERKO uterus at 60% of the level measured in a wild-type uterus. The PR-A and PR-B isoforms are both detected on Western blot, and the ratio of isoforms is the same in both genotypes. Although the level of PR is reduced in the ERKO uterus, the receptor level is sufficient to induce genomic responses, since both calcitonin and amphiregulin mRNAs were increased after progesterone treatment. Finally, the ERKO uterus can be induced to undergo a progesterone-dependent decidual response. Surprisingly, the decidual response is estrogen independent in the ERKO, although it remains estrogen dependent in a wild type. These results indicate that estrogen receptor ␣ modulation of PR levels is not necessary for expression of the PR or genomic and physiologic responses to progesterone in the ERKO uterus.
Expression and Localization of the Progesterone Receptor In Mouse and Human Reproductive Organs
Journal of …, 2006
The effects of gonadotropins on progesterone receptor (PR) expression and localization in the mouse oviduct, uterus, and ovary was examined. In the oviduct ciliated epithelial cells of adult mice and human revealed a unique PR localization to the lower half of the motile cilia whereas the nuclei were unstained or faintly stained. Pubertal female mice were further studied by confocal laser scanning microscopy and western blotting before and after injection with FSH and LH followed by human chorionic gonadotropin (hCG) injection after a 48-h period. PR immunolocalization to the oviduct cilia was greatly increased in pubertal mice upon hCG stimulation. In neighboring goblet cells, the PR staining was confined to the nuclei. Nuclear PR localization was evident in epithelial cells of the uterus as well as in a fraction of stromal and muscle cells. Staining intensity and number of stained cells was not affected by hormone stimulation. In the ovary, weak PR immunolocalization was observed in unprimed animals but increased significantly after hCG stimulation. In granulosa cells of preovulatory follicles PR was exclusively observed in mural cells, whereas cumulus cells remained negative. At all stages examined, primary granulosa cell cilia lacked PR staining. SDS-PAGE and western blotting analysis of tissues from oviduct, uterus, and ovary confirmed antibody specificity, and identified two bands corresponding to the PR isoforms PR-A and PR-B. Upon hCG stimulation, a new band cross-reacting with anti-PR emerged above the PR-A form in oviduct fractions, suggesting LH-induced phosphorylation of PR-A. We suggest that ciliary PR in the oviduct plays a role in progesterone signaling after ovulation, possibly via non-genomic events. These novel findings warrant further studies of oviduct and postovulatory signaling events and suggest a sensory role for oviduct cilia in the process of oocyte transport/fertilization.
Progesterone action and responses in the αERKO mouse
Steroids, 2000
Ovarian steroids have important inter-related roles in many systems and processes required for mammalian reproduction. The female reproductive tract, ovaries, and mammary glands are all targets for both estrogen and progesterone. In addition, the actions of these hormones are intertwined in that, for example, progesterone attenuates the proliferative effect of estrogen in the uterus, whereas estrogen also induces the progesterone receptor (PR) mRNA and protein, thus enhancing progesterone actions. The generation of mice that lacks the progesterone receptor (PRKO) or the estrogen receptor␣ (␣ERKO) has provided numerous insights into the interacting roles of these hormones. The mammary glands of the PRKO mice develop with full epithelial ducts that lack side branching and lobular alveolar structures, whereas the ␣ERKO mice develop only an epithelial rudiment. This indicates that estrogen is important for ductal morphogenesis, whereas progesterone is required for ductal branching and alveolar development. Both the ␣ERKO and PRKO mice are also anovulatory, but exhibit different causal pathologies. The ␣ERKO ovary seems to possess follicles up to the preantral stage and shows a polycystic phenotype as a result of chronic hyperstimulation by LH. The PRKO follicles seem to develop to an ovulatory stage, but are unable to rupture, indicating a role for progesterone in ovulation. The uteri of these two strains seem to develop normally; however, the function and hormone responses are abnormal in each. Because estrogen is known to induce PRs in the uterus, the progesterone responsiveness of the ␣ERKO uterus was characterized. PR mRNA was detected but was not up-regulated by estrogen in the ␣ERKO tissue. PRs are present in the ␣ERKO tissue at 60% of the level in wild-type tissue and show a similar amount of A and B isoforms when measured by R5020 binding and detected by Western blotting. The PRs were able to mediate induction of two progesteroneresponsive uterine genes: calcitonin and amphiregulin. The ␣ERKO uterine tissue was also able to undergo a decidual reaction in response to hormonal and intraluminal treatments to mimic implantation; however, unlike normal wild-type uteri, this response was estrogen independent in the ␣ERKO uterine tissue.