Progesterone receptors in reproduction: functional impact of the A and B isoforms

doi:10.1016/S0039-128X(00)00115-X

Steroids

Volume 65, Issues 10–11, October–November 2000, Pages 571-577

https://doi.org/10.1016/S0039-128X(00)00115-X Get rights and content

Abstract

Progesterone (P) is a key regulator of female reproductive activity. The effects of P are mediated by two progesterone receptor (PR) proteins, termed A and B, that arise from a single gene and act as ligand-activated transcription factors to regulate the expression of reproductive target genes. Null mutation of the PR gene in mice (PRKO) leads to pleiotropic reproductive abnormalities. This paper will review the reproductive functions of PRs delineated using the PRKO mouse. Further, we will summarize the structure and functional properties of PRs and discuss how functional differences between the PR-A and PR-B isoforms are likely to impact on the overall physiological role of the receptor in reproductive systems.

Introduction

Progesterone is an essential regulator of the reproductive events associated with the establishment and maintenance of pregnancy, including ovulation, uterine and mammary gland development, and the neurobehavioral expression associated with sexual responsiveness [1], [2]. The physiological effects of progesterone are mediated by interaction with specific intracellular proteins termed progesterone receptors (PRs). Recently, we demonstrated that the PR is absolutely essential for the female reproductive activities associated with progesterone by generating null mutant mice in which the expression of the PR gene was ablated [2]. These mice displayed pleiotropic reproductive abnormalities that underscored the critical role of PR in mammalian reproduction.

The PR is a transcription factor and a member of a large family of structurally related gene products known as the nuclear receptor superfamily [3], [4], [5], [6]. The PR is composed of two protein isoforms, termed A and B. Both isoforms are expressed from a single gene in rodents and humans as a result of transcription from two alternative promoters and translation initiation at two different AUG codons [7], [8]. The selective physiological roles of the two isoforms of PR are predicted to differ based on different structural and functional properties of the individual proteins observed using in vitro assay systems. In the following sections, we will summarize the structural and functional significance of the PR isoforms and will highlight the functional differences between the two proteins observed in vitro. Then, we will review the physiological role of PRs in reproduction and discuss how the functional differences between the two PR isoforms observed in vitro are likely to impact on the physiological role of the progesterone in reproductive systems.

Section snippets

Structure and functional properties of PRs

Binding of progesterone to PRs induces a significant conformational change on the proteins [9], [10] that results in: 1) homodimerization of two ligand receptor complexes [11], [12], [13], 2) increased receptor phosphorylation [14], [15]; 3) binding of receptor dimers to specific hormone responsive DNA elements located in the promoter regions of target genes [4], [16]; and 4) interaction of the receptor complex with specific coactivator proteins and general transcripton factors [17], [18] to

Structural and functional significance of the PR-A and -B protein isoforms

The PR-A and -B isoforms are expressed in a number of vertebrate species, including humans and rodents [43], [44], [45], [46], [47]. Two distinct promoters have been identified that are independently regulated and give rise to the A and B isoforms [7], [8]. The absolute levels of PR as well as the stoichiometric ratio of PR-A to PR-B in reproductive tissues vary as a consequence of developmental and hormonal status. The conservation of these two receptor isoforms and the complex genomic

Physiological role of PRs

To directly address the role of PRs in reproductive function, we previously generated a mouse model (PRKO) in which both isoforms of the PR were ablated by PR gene targeting. This model has provided definitive proof that PRs are essential coordinators of all reproductive events that together culminate in preparation for and maintenance of pregnancy [2]. In the following summary of the physiological role of PRs, we will focus on those aspects of progesterone-dependent reproductive function that

PRs and ovarian function

Evidence for a direct role of PRs in ovarian function has been supported in recent years by the demonstration that 1) the antiprogestin RU486 inhibits ovulation [56] and 2) that luteinizing hormone (LH), the primary signal for rupture of preovulatory ovarian follicles, can stimulate transient expression of PR mRNAs and both protein isoforms in granulosa cells isolated form preovulatory follicles [57], [58], [59]. Definitive proof that PRs are essential mediators of ovulation has been provided

PR and uterine development

The uterus is composed of heterogeneous cell types that undergo continuous synchronized waves of proliferation and differentiation in response to the cyclical rise and fall of estrogen and progesterone. PRs are expressed in the epithelial, stromal, and myometrial compartments of the uterus, and their spatiotemporal expression in these compartments is controlled by estrogen [1], [61], [62]. The primary proliferative stimulus in the epithelial compartment is estrogen [63], [64], [65], while

PR and mammary gland development

Progesterone and estrogen are the principle steroid hormones involved in normal breast development and tumorigenesis [71], [72]. Early ductal outgrowth observed postnatally is strongly controlled by estrogen acting through the ERα receptor localized in the stromal compartment of the mammary gland [73]. During pregnancy, increased branching, alveolar proliferation, and differentiation of alveolar lobules is controlled primarily by progesterone. Studies with the PRKO mouse [2] have confirmed

PR and sexual behavior

The preoptic areas, ventromedial nucleus (VMNH) of the hypothalmus and amygdala, have long been associated with a female sexual response exhibited by rodents, termed lordosis, and these areas express PRs [87], [88]. The lordosis response is characterized by a concave arching of the back with rump and head elevated to facilitate copulation by the male. The VMNH is primarily responsible for coordinating this sexual behavior with reproductive condition in order to optimize the chances for

Summary

Analysis of the reproductive phenotypes of the PRKO mouse has provided unequivocal evidence of the central role of the PR proteins in the coordination of all aspects of reproductive function. Our recent generation of new mutant strains of mice, in which the PR-A or -B proteins have been selectively ablated, now permits us to address the specific contributions of each PR isoform to the overall physiological role of progesterone. Preliminary phenotypic analysis of these mice has already provided

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