scholarly journals Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse

2006 ◽  
Vol 26 (17) ◽  
pp. 6571-6583 ◽  
Author(s):  
Atish Mukherjee ◽  
Selma M. Soyal ◽  
Rodrigo Fernandez-Valdivia ◽  
Martine Gehin ◽  
Pierre Chambon ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Embryo Implantation ◽  
Steroid Receptor ◽  
Ovarian Activity ◽  
Mouse Uterus ◽  
Steroid Receptor Coactivator ◽  
Mammary Morphogenesis ◽  
Uterine Function ◽  
And Function

ABSTRACT Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR Cre/+ SRC-2 flox/flox) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR Cre/+ SRC-2 flox/flox mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR Cre/+ SRC-2 flox/flox mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR Cre/+ SRC-2 flox/flox mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR Cre/+ SRC-2 flox/flox mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.

scholarly journals Steroid Receptor Coactivator 2 is Required for Female Fertility and Mammary Morphogenesis: Insights from the Mouse, Relevance to the Human

2007 ◽  
Vol 5 (1) ◽  
pp. nrs.05011 ◽  
Author(s):  
Atish Mukherjee ◽  
Paula Amato ◽  
D. Craig Allred ◽  
Francesco J. DeMayo ◽  
John P. Lydon
Keyword(s):  
Mammary Gland ◽  
Gene Knockout ◽  
Embryo Implantation ◽  
Cell Types ◽  
Steroid Receptor ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Signaling Cascades ◽  
Steroid Receptor Coactivator ◽  
Female Reproductive Health

Although the importance of the progesterone receptor (PR) to female reproductive and mammary gland biology is firmly established, the coregulators selectively co-opted by PR in these systems have not been clearly delineated. A selective gene-knockout approach applied to the mouse, which abrogates gene function only in cell types that express PR, recently disclosed steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) to be an indispensable coregulator for uterine and mammary gland responses that require progesterone. Uterine cells positive for PR (but devoid of SRC-2) were found to be incapable of facilitating embryo implantation, a necessary first step toward the establishment of the materno-fetal interface. Importantly, such an implantation defect is not exhibited by knockouts for SRC-1 or SRC-3, underscoring the unique coregulator importance of SRC-2 in peri-implantation biology. Moreover, despite normal levels of PR, SRC-1 and SRC-3, progesterone-dependent branching morphogenesis and alveologenesis fails to occur in the murine mammary gland in the absence of SRC-2, thereby establishing a critical coregulator role for SRC-2 in signaling cascades that mediate progesterone-induced mammary epithelial proliferation. Finally, the recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer.

scholarly journals Genetic Ablation of the Steroid Receptor Coactivator-Ubiquitin Ligase, E6-AP, Results in Tissue-Selective Steroid Hormone Resistance and Defects in Reproduction

2002 ◽  
Vol 22 (2) ◽  
pp. 525-535 ◽  
Author(s):  
Carolyn L. Smith ◽  
Darryll G. DeVera ◽  
Dolores J. Lamb ◽  
Zafar Nawaz ◽  
Yong-Hui Jiang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Ubiquitin Ligase ◽  
Steroid Hormone ◽  
Steroid Receptor ◽  
Null Mouse ◽  
Wild Type ◽  
Male And Female ◽  
Genetic Ablation ◽  
Steroid Receptor Coactivator

ABSTRACT The E6-associated protein (E6-AP), although originally identified as a ubiquitin ligase, has recently been shown to function as a coactivator of steroid receptor-dependent gene expression in in vitro assays. In order to determine whether E6-AP acts as a coactivator in vivo, physiological parameters associated with male and female sex steroid action were assessed in the E6-AP null mouse. Gonadal size was reduced in E6-AP null male and female mice in comparison to wild-type controls in conjunction with reduced fertility in both genders. Consistent with this observation, defects in sperm production and function, as well as ovulation were observed. In comparison to wild-type controls, induction of prostate gland growth induced by testosterone and uterine growth by estradiol were significantly reduced. In contrast, estrogen and progesterone-stimulated growth of virgin mammary gland was not compromised by E6-AP ablation despite E6-AP expression in this tissue. This latter finding contrasts with the impaired estrogen and progesterone-induced mammary gland development observed previously for steroid receptor coactivator type 1 (SRC-1) and SRC-3 female knockout mice. Taken together, these results are consistent with a role for E6-AP in mediating a subset of steroid hormone actions in vivo. Nevertheless, differences observed between SRC and E6-AP knockout phenotypes indicate that these two families of steroid receptor coactivators are not functionally equivalent and supports the hypothesis that coactivators contribute to tissue-specific steroid hormone action.

Inhibition of TMEM16A impedes embryo implantation and decidualization in mice

Reproduction ◽  
2018 ◽  
Author(s):  
Qianrong Qi ◽  
Yifan Yang ◽  
Kailin Wu ◽  
Qingzhen Xie
Keyword(s):  
Progesterone Receptor ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Mouse Uterus ◽  
Endometrial Stromal Cells ◽  
Uterine Endometrium ◽  
Molecule Inhibitor ◽  
Pathway Inhibition ◽  
And Function ◽  
Reproductive Processes

Recent studies revealed that TMEM16A is involved in several reproductive processes, including ovarian estrogen secretion and ovulation, sperm motility and acrosome reaction, fertilization, and myometrium contraction. However, little is known about the expression and function of TMEM16A in embryo implantation and decidualization. In this study, we focused on the expression and regulation of TMEM16A in mouse uterus during early pregnancy. We found that TMEM16A is up-regulated in uterine endometrium in response to embryo implantation and decidualization. Progesterone treatment could induce TMEM16A expression in endometrial stromal cells through progesterone receptor/c-Myc pathway, which is blocked by progesterone receptor antagonist or the inhibitor of c-Myc signaling pathway. Inhibition of TMEM16A by small molecule inhibitor (T16Ainh-A01) resulted in impaired embryo implantation and decidualization in mice. Treatment with either specific siRNA of Tmem16a or T16Ainh-A01 inhibited the decidualization and proliferation of mouse endometrial stromal cells. In conclusion, our results revealed that TMEM16A is involved in embryo implantation and decidualization in mice, compromised function of TMEM16A may lead to impaired embryo implantation and decidualization.

scholarly journals Forkhead box a2 (FOXA2) is essential for uterine function and fertility

2017 ◽  
Vol 114 (6) ◽  
pp. E1018-E1026 ◽  
Author(s):  
Andrew M. Kelleher ◽  
Wang Peng ◽  
James K. Pru ◽  
Cindy A. Pru ◽  
Francesco J. DeMayo ◽  
...  
Keyword(s):  
Stromal Cell ◽  
Adult Mouse ◽  
Embryo Implantation ◽  
Critical Event ◽  
Mouse Uterus ◽  
Forkhead Box ◽  
Uterine Gland ◽  
Blastocyst Implantation ◽  
Uterine Function ◽  
Uterine Glands

Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.

YY1 and RTCB in mouse uterine decidualization and embryo implantation

Reproduction ◽  
2021 ◽  
Author(s):  
Ran Li ◽  
Xiao-Tong Song ◽  
Si-Wei Guo ◽  
Na Zhao ◽  
Mei He ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Embryo Implantation ◽  
Mrna Splicing ◽  
Proximal Promoter ◽  
Mouse Uterus ◽  
Rna Ligase ◽  
Xbp1 Mrna ◽  
Transcription Factor Yy1

As a multifunctional transcription factor, YY1 regulates the expression of many genes essential for early embryonic development. RTCB is an RNA ligase that plays a role in tRNA maturation and Xbp1 mRNA splicing. YY1 can bind in vitro to the response element in the proximal promoter of Rtcb and regulate Rtcb promoter activity. However, the in vivo regulation and whether these two genes are involved in the mother-fetal dialogue during early pregnancy remain unclear. In this study, we validated that YY1 bound in vivo to the proximal promoter of Rtcb in mouse uterus of early pregnancy. Moreover, via building a variety of animal models, our study suggested that both YY1 and RTCB might play a role in mouse uterus decidualization and embryo implantation during early pregnancy.

scholarly journals HB-EGF regulates Prss56 expression during mouse decidualization via EGFR/ERK/EGR2 signaling pathway

2017 ◽  
Vol 234 (3) ◽  
pp. 247-254 ◽  
Author(s):  
Jie Liu ◽  
Fei Gao ◽  
Yue-Fang Liu ◽  
Hai-Ting Dou ◽  
Jia-Qi Yan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Implantation Site ◽  
Mouse Uterus ◽  
Delayed Implantation ◽  
Initial Stage ◽  
And Function ◽  
Key Steps

Embryo implantation and decidualization are key steps for successful reproduction. Although numerous factors have been identified to be involved in embryo implantation and decidualization, the mechanisms underlying these processes are still unclear. Based on our preliminary data, Prss56, a trypsin-like serine protease, is strongly expressed at implantation site in mouse uterus. However, the expression, regulation and function of Prss56 during early pregnancy are still unknown. In mouse uterus, Prss56 is strongly expressed in the subluminal stromal cells at implantation site on day 5 of pregnancy compared to inter-implantation site. Under delayed implantation, Prss56 expression is undetected. After delayed implantation is activated by estrogen, Prss56 is obviously induced at implantation site. Under artificial decidualization, Prss56 signal is seen at the primary decidual zone at the initial stage of artificial decidualization. When stromal cells are induced for in vitro decidualization, Prss56 expression is significantly elevated. Dtprp expression under in vitro decidualization is suppressed by Prss56 siRNA. In cultured stromal cells, HB-EGF markedly stimulates Prss56 expression through EGFR/ERK pathway. Based on promoter analysis, we also showed that Egr2 is involved in Prss56 regulation by HB-EGF. Collectively, Prss56 expression at implantation site is modulated by HB-EGF/EGFR/ERK signaling pathway and involved in mouse decidualization.

scholarly journals Fibroblast Growth Factor Receptor Two (FGFR2) Regulates Uterine Epithelial Integrity and Fertility in Mice

2014 ◽  
Vol 90 (1) ◽  
Author(s):  
Justyna Filant ◽  
Franco J. DeMayo ◽  
James K. Pru ◽  
John P. Lydon ◽  
Thomas E. Spencer
Keyword(s):  
Reproductive Tract ◽  
Embryo Implantation ◽  
Growth Factor Receptor ◽  
Mutant Mice ◽  
Fibroblast Growth ◽  
Basal Cells ◽  
Normal Numbers ◽  
Mouse Uterus ◽  
Mutant Female ◽  
And Function

Abstract Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate luminal epithelial (LE) cell proliferation in the adult mouse uterus. This study tested the hypothesis that FGFR2 has a biological role in postnatal development and function of the uterus by conditionally deletingFgfr2 after birth using progesterone receptor (Pgr)-Cre mice. AdultFgfr2 mutant female mice were initially subfertile and became infertile with increasing parity. No defects in uterine gland development were observed in conditionalFgfr2 mutant mice. In the adult,Fgfr2 mutant mice possessed a histologically normal reproductive tract with the exception of the uterus. The LE of theFgfr2 mutant uterus was stratified, but no obvious histological differences were observed in the glandular epithelium, stroma, or myometrium. Within the stratified LE, cuboidal basal cells were present and positive for basal cell markers (KRT14 and TRP63). Nulliparous bredFgfr2 mutants contained normal numbers of blastocysts on Day 3.5 postmating, but the number of embryo implantation sites was substantially reduced on Day 5.5 postmating. These results support the idea that loss of FGFR2 in the uterus after birth alters its development, resulting in LE stratification and peri-implantation pregnancy loss.

scholarly journals Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization

2015 ◽  
Vol 112 (49) ◽  
pp. 15166-15171 ◽  
Author(s):  
Shannon D. Whirledge ◽  
Robert H. Oakley ◽  
Page H. Myers ◽  
John P. Lydon ◽  
Francesco DeMayo ◽  
...  
Keyword(s):  
Glucocorticoid Receptors ◽  
Reproductive Tract ◽  
Immune Cell ◽  
Steroid Receptors ◽  
Embryo Implantation ◽  
Female Reproductive Tract ◽  
Mouse Uterus ◽  
Glucocorticoid Signaling ◽  
Endocrine Organs

In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic–pituitary–adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PRcre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions.

Sign in / Sign up

Export Citation Format

Share Document