Uterine Development and Fertility Are Dependent on Gene Dosage of the Nuclear Receptor Coregulator REA
ABSTRACT Although the effectiveness of nuclear hormone-receptor complexes is known to depend on coregulator partner proteins, relatively little is known about the roles of coregulators in uterine development and early stages of pregnancy and implantation. Because conventional genetic deletion of the coregulator, repressor of estrogen receptor activity (REA), was embryonic lethal, we here study REA conditional knockout mice generated by cre-loxP recombination, in which REA function was abrogated only in progesterone receptor-expressing tissues, to define the roles of REA in postembryonic stages and in a tissue-specific manner. We find that REA has gene dose-dependent activity impacting uterine development and fertility. Conditional homozygous mutant (REA(d/d)) mice developed to adulthood and showed normal ovarian function, but females were infertile with severely compromised uterine development and function characterized by cell cycle arrest, apoptosis, and altered adenogenesis (endometrial gland morphogenesis), resulting in failure of implantation and decidualization. By contrast, mice heterozygous for REA (REA(f/d)) had a very different phenotype, with estradiol treatment resulting in hyperstimulated, large uteri showing increased proliferation of luminal epithelial cells, and enhanced fluid imbibition associated with altered regulation of aquaporins. These REA(f/d) female mice showed a subfertility phenotype with reduced numbers and sizes of litters. These findings highlight that uterine development and regulation of estrogen receptor activities show a bimodal dependence on the gene dosage of REA. Optimal uterine development and functional activities require the normal gene dosage of REA, with partial or complete deletion resulting in hyperresponsiveness or underresponsiveness to hormone and subfertility or infertility, respectively.
SourceAvailable from: Katherine V Clark-Knowles[Show abstract] [Hide abstract]
ABSTRACT: The protein deacetylase SIRT1 is involved in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. Both SIRT1 activity and tumorigenesis can be influenced by dietary fat and polyphenolics. We set out to determine whether dietary modulations of tumorigenesis are mediated by SIRT1 catalytic functions. We introduced a mammary gland tumor-inducing transgene, MMTV-PyMT, into stocks of mice bearing a H355Y point mutation in the Sirt1 gene that abolishes SIRT1 catalytic activity. Tumor latency was reduced in animals fed a high fat diet but this effect was not dependent on SIRT1 activity. Resveratrol had little effect on tumor formation except in animals heterozygous for the mutant Sirt1 gene. We conclude that the effects of these dietary interventions on tumorigenesis are not mediated by modulation of SIRT1 catalytic activity.PLoS ONE 11/2014; 9(11):e112406. DOI:10.1371/journal.pone.0112406 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The p160/steroid receptor coactivator (SRC) family comprises three pleiotropic coregulators (SRC-1, -2, and -3; otherwise known as NCOA1, NCOA2, NCOA3), which modulate a wide spectrum of physiological responses and clinicopathologies. Such pleiotropy is achieved through their inherent structural complexity, which allows this coregulator class to control both nuclear receptor (NR) and non-NR signaling. As observed in other physiologic systems, members of the SRC family have recently been shown to play pivotal roles in uterine biology and pathobiology. In the murine uterus, SRC-1 is required to launch a full steroid hormone response, without which endometrial decidualization is markedly attenuated. From "dove-tailing" clinical and mouse studies, an isoform of SRC-1 was recently identified which promotes endometriosis by reprogramming endometrial cells to evade apoptosis and colonize as endometriotic lesions within the peritoneal cavity. The endometrium fails to decidualize without SRC-2, which accounts for the infertility phenotype exhibited by mice devoid of this coregulator. In related studies on human endometrial stromal cells (ESCs), SRC-2 was shown to act as a molecular "pace maker" of the glycolytic flux. This finding is significant as acceleration of the glycolytic flux provides the necessary bioenergy and biomolecules for ESCs to switch from quiescence to a proliferative phenotype, a critical underpinning in the decidual progression program. Though studies on uterine SRC-3 function are in their early stages, clinical studies provide tantalizing support for the proposal that SRC-3 is causally linked to endometrial hyperplasia as well as with endometrial pathologies in patients diagnosed with polycystic ovary syndrome. This proposal is now driving the development and application of innovative technologies particularly in the mouse to further understand the functional role of this elusive uterine coregulator in normal and abnormal physiologic contexts. Because dysregulation of this coregulator triad potentially presents a triple threat for increased risk of subfecundity, infertility, or endometrial disease, a clearer understanding of the individual and combinatorial roles of these coregulators in uterine function is urgently required. This minireview summarizes our current understanding of uterine SRC function, with a particular emphasis on the next critical questions that need to be addressed to ensure significant expansion of our knowledge of this underexplored field of uterine biology.Biology of Reproduction 10/2014; DOI:10.1095/biolreprod.114.125021 · 3.45 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Implantation is an essential process during establishment of pregnancy in mammals. It is initiated with the attachment of the blastocyst to a receptive uterine epithelium followed by its invasion into the stromal tissue. These events are profoundly regulated by the steroid hormones 17β-estradiol (E) and progesterone (P). During the past several years, mouse models harboring conditional gene knockout mutations have become powerful tools for determining the functional roles of cellular factors involved in various aspects of implantation biology. Studies employing these genetic models as well as primary cultures of human endometrial cells have established that the estrogen receptor alpha (ESR1), the progesterone receptor (PGR), and their downstream target genes critically regulate uterine growth and differentiation, which in turn control embryo-endometrial interactions during early pregnancy. These studies have uncovered a diverse array of molecular cues, which are produced under the influence of ESR1 and PGR and exchanged between the epithelial and stromal compartments of the uterus during the progressive phases of implantation. These paracrine signals are critical for acquisition of uterine receptivity and functional interactions with the embryo. This review highlights recent work describing paracrine mechanisms that govern steroid-regulated uterine stromal-epithelial dialogue during implantation and their roles in fertility and disease.Molecular Endocrinology 07/2014; 28(9):me20141074. DOI:10.1210/me.2014-1074 · 4.20 Impact Factor