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Thomas E Spencer - One of the best experts on this subject based on the ideXlab platform.
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Sexually dimorphic effects of forkhead box a2 (FOXA2) and Uterine Glands on decidualization and fetoplacental development
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Pramod Dhakal, Susanta K. Behura, Andrew M. Kelleher, Thomas E SpencerAbstract:Glands of the uterus are essential for pregnancy establishment. Forkhead box A2 (FOXA2) is expressed specifically in the Glands of the uterus and a critical regulator of Glandular epithelium (GE) differentiation, development, and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with Glands, but lack FOXA2-dependent GE-expressed genes, such as leukemia inhibitory factor (LIF). Adult FOXA2 conditional knockout (cKO; Ltf iCre/+ Foxa2 f/f ) mice are infertile due to defective embryo implantation arising from a lack of LIF, a critical implantation factor of Uterine Gland origin. However, intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the Uterine Glands impact development of the decidua, placenta, and fetus. On gestational day 8.5, the antimesometrial and mesometrial decidua transcriptome was noticeably altered in LIF-replaced FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on gestational days 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial Gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and Uterine Glands on fetoplacental development with potential impacts on offspring health into adulthood.
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Uterine Glands: Developmental Biology and Functional Roles in Pregnancy.
Endocrine reviews, 2019Co-Authors: Andrew M. Kelleher, Francesco J. Demayo, Thomas E SpencerAbstract:All mammalian uteri contain Glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell-cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary Gland. The infertility and recurrent pregnancy loss observed in Uterine Gland knockout sheep and mouse models support a primary role for secretions and products of the Glands in pregnancy success. Recent studies in mice revealed that Uterine Glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, Uterine Glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal-maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the Uterine Glands during pregnancy. This review summarizes new information related to the developmental biology of Uterine Glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
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Development and Function of Uterine Glands in Domestic Animals.
Annual review of animal biosciences, 2018Co-Authors: Thomas E Spencer, Andrew M. Kelleher, Frank F BartolAbstract:All mammalian uteri contain Glands that synthesize or transport and secrete substances into the Uterine lumen. Uterine Gland development, or adenogenesis, is uniquely a postnatal event in sheep and...
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Forkhead box a2 (FOXA2) is essential for Uterine function and fertility
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Andrew M. Kelleher, Wang Peng, James K. Pru, Cindy A Pru, Francesco J. Demayo, Thomas E SpencerAbstract: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.
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Uterine Glands impact Uterine receptivity, luminal fluid homeostasis and blastocyst implantation
Scientific reports, 2016Co-Authors: Andrew M. Kelleher, Gregory W. Burns, Susanta K. Behura, Thomas E SpencerAbstract:Uterine Glands are essential for pregnancy in mice and likely humans, because they secrete or transport bioactive substances that regulate Uterine receptivity for blastocyst implantation. In mice, the uterus becomes receptive to blastocyst implantation on day 4, but is refractory by day 5. Here, blastocysts could be recovered from progesterone-induced Uterine Gland (PUGKO) but not wildtype (WT) mice on day 5 post-mating. Anti-adhesive Muc1 protein and microvilli were present on the luminal epithelium of PUGKO but not WT uteri. A number of known Uterine receptivity genes and Gland-specific genes were altered in the PUGKO uterus. Next, the uterus and Uterine luminal fluid (ULF) were obtained from WT and PUGKO mice on day 3, 4 and 5. Transcriptome analysis revealed that 580 genes were decreased in the PUGKO uterus, however ULF secrotome analysis revealed that many proteins and several amino acids were increased in the PUGKO ULF. Of note, many proteins encoded by many Gland-specific genes were not identified in the ULF of WT mice. These results support the ideas that Uterine Glands secrete factors that regulate ULF homeostasis and interact with other cell types in the uterus to influence Uterine receptivity and blastocyst implantation for the establishment of pregnancy.
Frank F Bartol - One of the best experts on this subject based on the ideXlab platform.
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Development and Function of Uterine Glands in Domestic Animals.
Annual review of animal biosciences, 2018Co-Authors: Thomas E Spencer, Andrew M. Kelleher, Frank F BartolAbstract:All mammalian uteri contain Glands that synthesize or transport and secrete substances into the Uterine lumen. Uterine Gland development, or adenogenesis, is uniquely a postnatal event in sheep and...
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Uterine Glands: development, function and experimental model systems
Molecular human reproduction, 2013Co-Authors: Paul S. Cooke, Thomas E Spencer, Frank F Bartol, Kanako HayashiAbstract:Development of Uterine Glands (adenogenesis) in mammals typically begins during the early post-natal period and involves budding of nascent Glands from the luminal epithelium and extensive cell proliferation in these structures as they grow into the surrounding stroma, elongate and mature. Uterine Glands are essential for pregnancy, as demonstrated by the infertility that results from inhibiting the development of these Glands through gene mutation or epigenetic strategies. Several genes, including forkhead box A2, beta-catenin and members of the Wnt and Hox gene families, are implicated in Uterine Gland development. Progestins inhibit Uterine epithelial proliferation, and this has been employed as a strategy to develop a model in which progestin treatment of ewes for 8 weeks from birth produces infertile adults lacking Uterine Glands. More recently, mouse models have been developed in which neonatal progestin treatment was used to permanently inhibit adenogenesis and adult fertility. These studies revealed a narrow and well-defined window in which progestin treatments induced permanent infertility by impairing neonatal Gland development and establishing endometrial changes that result in implantation defects. These model systems are being utilized to better understand the molecular mechanisms underlying Uterine adenogenesis and endometrial function. The ability of neonatal progestin treatment in sheep and mice to produce infertility suggests that an approach of this kind may provide a contraceptive strategy with application in other species. Recent studies have defined the temporal patterns of adenogenesis in uteri of neonatal and juvenile dogs and work is underway to determine whether neonatal progestin or other steroid hormone treatments might be a viable contraceptive approach in this species.
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lactation biology symposium lactocrine signaling and developmental programming
Journal of Animal Science, 2013Co-Authors: Frank F Bartol, Anne A Wiley, Dori J Miller, Alejandro J Silva, K E Roberts, M L P Davolt, Joseph C Chen, Amylynn Frankshun, Meredith E Camp, Kathleen M RahmanAbstract:Lactocrine signaling is defi ned as transmission of bioactive factors from mother to offspring as a consequence of nursing. Lactocrine transmission of signaling molecules may be an evolutionarily conserved process through which bioactive factors necessary for support of neonatal development are delivered postnatally. Dependence on maternal resources for development in eutherian mammals extends into neonatal life for at least that period of time when nutrition is obtained solely from fi rst milk (i.e., colostrum). Data for the pig (Sus scrofa domesticus) provide evidence of lactocrine mediated effects on development of the female reproductive tract and other somatic tissues. Porcine Uterine Gland development, an estrogen receptor-alpha (ESR1)- dependent process, begins within 2 d of birth [postnatal day (PND) 0]. A lactocrine-driven, ESR1-mediated process was proposed as a regulatory mechanism governing onset of Uterine Gland development and endometrial maturation in the neonatal pig. Gilts maintained in a lactocrine-null state for 2 d from birth by milk-replacer feeding displayed altered patterns of endometrial gene expression and retarded Uterine Gland development by PND 14. In lactocrine-null gilts, inhibition of endometrial and cervical ESR1 and vascular endothelial growth factor (VEGFA) expression observed on PND 2 persisted to PND 14, even after gilts were returned to nursing on PND 2. Collectively, data support a role for lactocrine signaling in regulation of critical neonatal developmental events. Maternal lactocrine programming of postnatal development may help to insure healthy developmental outcomes. A systems biology approach will be required to define and understand mechanistic dynamics of lactocrine signaling events that may ultimately connect genotype to phenotype and establish the parameters of reproductive potential.
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nursing for 48 hours from birth supports porcine Uterine Gland development and endometrial cell compartment specific gene expression
Biology of Reproduction, 2013Co-Authors: Dori J Miller, Anne A Wiley, Joseph C Chen, Carol A Bagnell, Frank F BartolAbstract:ABSTRACT The first 2 wk of neonatal life constitute a critical period for estrogen receptor alpha (ESR1)-dependent Uterine adenogenesis in the pig. A relaxin receptor (RXFP1)-mediated, lactocrine-driven mechanism was proposed to explain how nursing could regulate endometrial ESR1 and related gene expression events associated with adenogenesis in the porcine neonate during this period. To determine effects of nursing on endometrial morphogenesis and cell compartment-specific gene expression, gilts (n = 6–8/group) were assigned at birth to be either 1) nursed ad libitum for 48 h, 2) gavage fed milk replacer for 48 h, 3) nursed ad libitum to Postnatal Day (PND) 14, or 4) gavage fed milk replacer for 48 h followed by ad libitum nursing to PND 14. Uteri were collected on PND 2 or PND 14. Endometrial histoarchitecture and both ESR1 and proliferating cell nuclear antigen (PCNA) labeling indexes (LIs) were evaluated. Laser microdissection was used to capture epithelium and stroma to evaluate treatment effects on ...
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Uterine Gland development begins postnatally and is accompanied by estrogen and progesterone receptor expression in the dog
Theriogenology, 2012Co-Authors: Paul S. Cooke, D.c. Borsdorf, G.c. Ekman, Karen F. Doty, S.g. Clark, P.j. Dziuk, Frank F BartolAbstract:During neonatal and juvenile life, mammalian uteri undergo extensive structural and functional changes, including Uterine Gland differentiation and development. In sheep and mice, inhibition of neonatal Uterine Gland development induced by progestin treatment led to a permanent aGlandular Uterine phenotype and adult infertility, suggesting that this strategy might be useful for sterilizing dogs and other companion animals. The goal of this study was to define temporal patterns of adenogenesis (Gland development), cell proliferation, and progesterone and estrogen receptor expression in uteri of neonatal and juvenile dogs as a first step toward determining whether neonatal progestin treatments might be a feasible contraceptive approach in this species. Uteri obtained from puppies at postnatal wk 1, 2, 4, 6, or 8 were evaluated histologically and immunostained for MKI67, a marker of cell proliferation, estrogen receptor-1, and progesterone receptor. Adenogenesis was under way at 1 wk of age, as indicated by the presence of nascent Glands beginning to bud from the luminal epithelium, and rapid proliferation of both luminal epithelial and stromal cells. By Week 2, Glands were clearly identifiable and proliferation of luminal, Glandular, and stromal cells was pronounced. At Week 4, increased numbers of endometrial Glands were evident penetrating Uterine stroma, even as proliferative activity decreased in all cell compartments as compared with Week 2. Whereas Gland development was most advanced at Weeks 6 to 8, luminal, Glandular, and stromal proliferation was minimal, indicating that the uterus was nearly mitotically quiescent at this age. Both estrogen receptor-1 and progesterone receptor were expressed consistently in Uterine stromal and epithelial cells at all ages examined. In summary, canine Uterine adenogenesis was underway by 1 wk of age and prepubertal Glandular proliferation was essentially complete by Week 6. These results provided information necessary to facilitate development of canine sterilization strategies based on neonatal progestin treatments designed to permanently inhibit Uterine Gland development and adult fertility.
Richard R. Behringer - One of the best experts on this subject based on the ideXlab platform.
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Epithelial morphogenesis in the perinatal mouse uterus
Developmental dynamics : an official publication of the American Association of Anatomists, 2020Co-Authors: Zer Vue, Richard R. BehringerAbstract:BACKGROUND The uterus is the location where multiple events occur that are required for the start of new life in mammals. The adult uterus contains endometrial or Uterine Glands that are essential for female fertility. In the mouse, Uterine Glands are located in the lateral and antimesometrial regions of the Uterine horn. Previous three-dimensional (3D)-imaging of the adult uterus, its Glands, and implanting embryos has been performed by multiple groups, using fluorescent microscopy. Adenogenesis, the formation of Uterine Glands, initiates after birth. Recently, we created a 3D-staging system of mouse Uterine Gland development at postnatal time points, using light sheet fluorescent microscopy. Here, using a similar approach, we examine the morphological changes in the epithelium of the perinatal mouse uterus. RESULTS The Uterine epithelium exhibits dorsoventral (mesometrial-antimesometrial) patterning as early as 3 days after birth (P3), marked by the presence of the dorsally positioned developing Uterine rail. Uterine Gland buds are present beginning at P4. Novel morphological epithelial structures, including a ventral ridge and Uterine segments were identified. CONCLUSIONS The perinatal mouse Uterine luminal epithelium develops dorsal-ventral morphologies at 3 to 4 days postpartum. Between 5 and 6 days postpartum Uterine epithelial folds form, defining alternating left-right segments.
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Epithelial morphogenesis in the perinatal mouse uterus
2020Co-Authors: Zer Vue, Richard R. BehringerAbstract:BackgroundThe uterus is the location where multiple events occur that are required for the start of new life in mammals. The adult uterus contains endometrial or Uterine Glands that are essential for female fertility. In the mouse, Uterine Glands are located in the lateral and anti-mesometrial regions of the Uterine horn. Previous 3D-imaging of the adult uterus, its Glands, and implanting embryos has been performed by multiple groups, using fluorescent microscopy. Adenogenesis, the formation of Uterine Glands, initiates after birth. Recently, we created a 3D-staging system of mouse Uterine Gland development at postnatal time points, using light sheet fluorescent microscopy. Here, using a similar approach, we examine the morphological changes in the epithelium of the perinatal mouse uterus. ResultsThe Uterine epithelium exhibits mesometrial-antimesometrial (dorsoventral) patterning as early as three days after birth (P3), marked by the presence of the mesometrially-positioned developing Uterine rail. Uterine Gland buds are present beginning at P4. Novel morphological epithelial structures, including a ventral ridge and Uterine segments were identified. ConclusionsThe perinatal mouse Uterine luminal epithelium develops mesometrial-antimesometrial (dorsal-ventral) morphologies at 3-4 days post-partum. Between 5-6 days post-partum Uterine epithelial folds form, defining alternating left-right segments. Bullet pointsO_LIMorphological patterning events in the perinatal Uterine epithelium are not well described. C_LIO_LILight sheet microscopy was used to generate volumetric reconstructions of the perinatal mouse Uterine epithelium. C_LIO_LIAt postnatal day 3 (P3), the Uterine epithelium shows the first signs of dorsoventral pattern, with the presence of the forming mesometrially-positioned Uterine rail. C_LIO_LIThe first morphological indication of Uterine adenogenesis begins at P4. C_LIO_LINovel morphological structures were identified from volumetric reconstructions, including the presence of a ventral ridge (another sign of dorsoventral pattern) and Uterine segmentation. C_LI
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Chronic estrus disrupts Uterine Gland development and homeostasis
2018Co-Authors: C. Allison Stewart, M. David Stewart, Ying Wang, Rui Liang, Yu Liu, Richard R. BehringerAbstract:Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on Uterine Gland biology. Although Uterine Gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By 20 weeks of age, Uterine Gland development was comparable to controls, but pathologies, including squamous neoplasia, tubal neoplasia, and cribriform Glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue post-pubertal Uterine Gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in post-pubertal Uterine Gland development. However, progesterone treatment did not rescue post-pubertal Uterine Gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts post-pubertal Uterine Gland development and homeostasis.
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Volumetric imaging of the developing prepubertal mouse Uterine epithelium using light sheet microscopy
Molecular reproduction and development, 2018Co-Authors: Zer Vue, C. Allison Stewart, Gabriel Gonzalez, Shyamin Mehra, Richard R. BehringerAbstract:Endometrial or Uterine Glands secrete substances essential for Uterine receptivity to the embryo, implantation, conceptus survival, and growth. Adenogenesis is the process of Gland formation within the stroma of the uterus. In the mouse, Uterine Gland formation initiates at postnatal day (P) 5. Uterine Gland morphology is poorly understood because it is primarily based on two-dimensional (2D) histology. To more fully describe Uterine Gland morphogenesis, we generated three-dimensional (3D) models of postnatal Uterine Glands from P0 to P21, based on volumetric imaging using light sheet microscopy. At birth (P0), there were no Glands. At P8, we found bud- and teardrop-shaped epithelial invaginations. By P11, the forming Glands were elongated epithelial tubes. By P21, the elongated tubes had a sinuous morphology. These morphologies are homogeneously distributed along the anterior-posterior axis of the uterus. To facilitate Uterine Gland analyses, we propose a novel 3D staging system of Uterine Gland morphology during development in the prepubertal mouse. We define five Uterine Gland stages: Stage 1: bud; Stage 2: teardrop; Stage 3: elongated; Stage 4: sinuous; and Stage 5: primary branches. This staging system provides a standardized key to assess and quantify prepubertal Uterine Gland morphology that can be used for studies of Uterine Gland development and pathology. In addition, our studies suggest that Gland formation initiation occurs during P8 and P11. However, between P11 and P21 Gland formation initiation stops and all Glands elongate and become sinuous. We also found that the mesometrial epithelium develops a unique morphology we term the Uterine rail.
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A three-dimensional staging system of mouse endometrial Gland morphogenesis
2018Co-Authors: Zer Vue, C. Allison Stewart, Gabriel Gonzalez, Shyamin Mehra, Richard R. BehringerAbstract:Endometrial or Uterine Glands secrete substances essential for Uterine receptivity to the embryo, implantation, conceptus survival, development, and growth. Adenogenesis is the process of Gland formation within the stroma of the uterus that occurs after birth. In the mouse, Uterine Gland formation initiates at postnatal day (P) 5. Subsequently, the developing Uterine Glands invade into the adjacent stroma. Mouse Uterine Gland morphology is poorly understood because it is based on two-dimensional (2D) histological observations. To more fully describe Uterine Gland morphogenesis, we generated three-dimensional (3D) models of postnatal Uterine Glands from P0 to P21, using light sheet microscopy. At birth (P0), there were no Glands. At P8, we found bud- and teardrop-shaped epithelial invaginations. By P11, the forming Glands were elongated epithelial tubes. By P21, the elongated tubes had a sinuous morphology. These morphologies are homogeneously distributed along the anterior-posterior axis of the uterus. To facilitate Uterine Gland analyses, we propose a novel 3D staging system of Uterine Gland morphology during postnatal development in the mouse. We define 6 stages: Stage 0: AGlandular, Stage 1: Bud, Stage 2: Teardrop, Stage 3: Elongated, Stage 4: Sinuous, and Stage 5: Primary Branches. This staging system provides a standardized key to assess and quantify Uterine Gland morphology that can be used for studies of Uterine Gland development and pathology. In addition, our studies suggest that Gland formation initiation occurs during P8 and P11. However, between P11 and P21 Gland formation initiation stops and all Glands elongate and become sinuous.
Jae Wook Jeong - One of the best experts on this subject based on the ideXlab platform.
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endometrial epithelial arid1a is critical for Uterine Gland function in early pregnancy establishment
The FASEB Journal, 2021Co-Authors: Ryan M Marquardt, Tae-hoon Kim, Jung-yoon Yoo, Hanna E. Teasley, Steven L. Young, Bruce A. Lessey, Asgerally T Fazleabas, Ripla Arora, Jae Wook JeongAbstract:Though endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial Gland function. Uterine-specific deletion of Arid1a compromises Gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves the Gland development while still compromising the Gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in nonhuman primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of Gland function.
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endometrial epithelial arid1a is critical for Uterine Gland function in early pregnancy establishment
bioRxiv, 2020Co-Authors: Ryan M Marquardt, Tae-hoon Kim, Jung-yoon Yoo, Hanna E. Teasley, Steven L. Young, Bruce A. Lessey, Asgerally T Fazleabas, Ripla Arora, Jae Wook JeongAbstract:Though endometriosis and infertility are clearly associated, the pathophysiological mechanism remains unclear. Previous work has linked endometrial ARID1A loss to endometriosis-related endometrial non-receptivity. Here, we show in mice that ARID1A binds and regulates transcription of the Foxa2 gene required for endometrial Gland function. Uterine specific deletion of Arid1a compromises Gland development and diminishes Foxa2 and Lif expression. Deletion of Arid1a with Ltf-iCre in the adult mouse endometrial epithelium preserves Gland development while still compromising Gland function. Mice lacking endometrial epithelial Arid1a are severely sub-fertile due to defects in implantation, decidualization, and endometrial receptivity from disruption of the LIF-STAT3-EGR1 pathway. FOXA2 is also reduced in the endometrium of women with endometriosis in correlation with diminished ARID1A, and both ARID1A and FOXA2 are reduced in non-human primates induced with endometriosis. Our findings describe a role for ARID1A in the endometrial epithelium supporting early pregnancy establishment through the maintenance of Gland function.
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Pik3ca is required for mouse Uterine Gland development and pregnancy.
PloS one, 2018Co-Authors: Hye Jin Chang, Hee Sung Shin, Tae-hoon Kim, Jung-yoon Yoo, Hanna E. Teasley, Jean J. Zhao, Jae Wook JeongAbstract:The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. The Pik3ca gene is mutated in a range of human cancers. It has been found to be oncogenic, and mutations lead to constitutive activation of the PI3K/AKT pathway. The expression patterns of PIK3CA proteins in the uterus of mice during early pregnancy indicate that it may play a role in the regulation of Glandular epithelial cells, which is required to support Uterine receptivity. To further investigate the role of Pik3ca in Uterine function, Pik3ca was conditionally ablated only in the PGR-positive cells (Pgrcre/+Pik3caf/f; Pik3cad/d). A defect of Uterine Gland development and decidualization led to subfertility observed in Pik3cad/d mice. Pik3cad/d mice showed significantly decreased Uterine weight compared to Pik3caf/f mice. Interestingly, a significant decrease of Gland numbers were detected in Pik3cad/d mice compared to control mice. In addition, we found a decrease of Foxa2 expression, which is a known Uterine Gland marker in Pik3cad/d mice. Furthermore, the excessive proliferation of endometrial epithelial cells was observed in Pik3cad/d mice. Our studies suggest that Pik3ca has a critical role in Uterine Gland development and female fertility.
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SOX17 regulates Uterine epithelial–stromal cross-talk acting via a distal enhancer upstream of Ihh
Nature Publishing Group, 2018Co-Authors: Xiaoqiu Wang, Tae-hoon Kim, Jae Wook Jeong, Tianyuan Wang, Steven L. Young, Bruce A. Lessey, Rainer B. Lanz, John P. LydonAbstract:The transcription factor SOX17 is important for Uterine Gland formation, fertility, and embryo implantation in mouse. Here the authors show that SOX17 is upstream of Indian hedgehog to regulate mouse Uterine receptivity, and their analysis of Uterine tissue from endometriosis patients suggests the same function in humans
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Abstract 94: The role ofPik3cain Uterine Gland morphogenesis and fertility in mice
Tumor Biology, 2014Co-Authors: Hee Sung Shin, Tae-hoon Kim, Jung-yoon Yoo, Jean J. Zhao, John P. Lydon, Jae Wook JeongAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Pik3ca mutations are frequently observed in endometrial carcinomas. Inappropriate activation of PI3Kα-mediated signaling results in increased AKT-dependent or AKT-independent signaling. The PI3K/AKT signaling pathway plays a critical role in the maintenance of equilibrium between cell survival and apoptosis. In order to investigate the role of Pik3ca in Uterine function and tumorigenesis, we generated a mouse model in which Pik3ca gene expression is ablated specifically in the PR-expressing cells (PRcre/+ Pik3caf/f). Ablation of Pik3ca was confirmed by real time PCR, western blot, and immunohistochemical analysis of the uteri. PRcre/+ Pik3caf/f mice were subfertile due to defective Uterine development. PRcre/+ Pik3caf/f mice showed significantly decreased Uterine weight compared Pik3caf/f mice at 2 months of age. Interestingly, PRcre/+ Pik3caf/f mice exhibited a defect of endometrial Gland development. Number of Glandular epithelia were significantly decreased in PRcre/+ Pik3caf/f mice compared to control Pik3caf/f mice. The expression of Foxa2, a specific Glandular epithelial marker, was significantly decreased in PRcre/+ Pik3caf/f mice and apoptosis was significantly increased in the luminal epithelium of PRcre/+ Pik3caf/f mice. These results indicate that Pik3ca plays a role in female fertility and Uterine development. (This work was supported by NIH U54 HD007495 to J.P.L, Basic Science Research Program (2010-0009047) funded by the MEST, Korea to U-H.H., and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG to J.W.J.) Citation Format: Heesung Shin, Tae Hoon Kim, Jung-Yoon Yoo, Jean J. Zhao, John P. Lydon, Un-Hwan Ha, Jae-Wook Jeong. The role of Pik3ca in Uterine Gland morphogenesis and fertility in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 94. doi:10.1158/1538-7445.AM2014-94
Andrew M. Kelleher - One of the best experts on this subject based on the ideXlab platform.
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Sexually dimorphic effects of forkhead box a2 (FOXA2) and Uterine Glands on decidualization and fetoplacental development
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Pramod Dhakal, Susanta K. Behura, Andrew M. Kelleher, Thomas E SpencerAbstract:Glands of the uterus are essential for pregnancy establishment. Forkhead box A2 (FOXA2) is expressed specifically in the Glands of the uterus and a critical regulator of Glandular epithelium (GE) differentiation, development, and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with Glands, but lack FOXA2-dependent GE-expressed genes, such as leukemia inhibitory factor (LIF). Adult FOXA2 conditional knockout (cKO; Ltf iCre/+ Foxa2 f/f ) mice are infertile due to defective embryo implantation arising from a lack of LIF, a critical implantation factor of Uterine Gland origin. However, intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the Uterine Glands impact development of the decidua, placenta, and fetus. On gestational day 8.5, the antimesometrial and mesometrial decidua transcriptome was noticeably altered in LIF-replaced FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on gestational days 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial Gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and Uterine Glands on fetoplacental development with potential impacts on offspring health into adulthood.
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Uterine Glands: Developmental Biology and Functional Roles in Pregnancy.
Endocrine reviews, 2019Co-Authors: Andrew M. Kelleher, Francesco J. Demayo, Thomas E SpencerAbstract:All mammalian uteri contain Glands in the endometrium that develop only or primarily after birth. Gland development or adenogenesis in the postnatal uterus is intrinsically regulated by proliferation, cell-cell interactions, growth factors and their inhibitors, as well as transcription factors, including forkhead box A2 (FOXA2) and estrogen receptor α (ESR1). Extrinsic factors regulating adenogenesis originate from other organs, including the ovary, pituitary, and mammary Gland. The infertility and recurrent pregnancy loss observed in Uterine Gland knockout sheep and mouse models support a primary role for secretions and products of the Glands in pregnancy success. Recent studies in mice revealed that Uterine Glandular epithelia govern postimplantation pregnancy establishment through effects on stromal cell decidualization and placental development. In humans, Uterine Glands and, by inference, their secretions and products are hypothesized to be critical for blastocyst survival and implantation as well as embryo and placental development during the first trimester before the onset of fetal-maternal circulation. A variety of hormones and other factors from the ovary, placenta, and stromal cells impact secretory function of the Uterine Glands during pregnancy. This review summarizes new information related to the developmental biology of Uterine Glands and discusses novel perspectives on their functional roles in pregnancy establishment and success.
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Development and Function of Uterine Glands in Domestic Animals.
Annual review of animal biosciences, 2018Co-Authors: Thomas E Spencer, Andrew M. Kelleher, Frank F BartolAbstract:All mammalian uteri contain Glands that synthesize or transport and secrete substances into the Uterine lumen. Uterine Gland development, or adenogenesis, is uniquely a postnatal event in sheep and...
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Forkhead box a2 (FOXA2) is essential for Uterine function and fertility
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Andrew M. Kelleher, Wang Peng, James K. Pru, Cindy A Pru, Francesco J. Demayo, Thomas E SpencerAbstract: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.
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Uterine Glands impact Uterine receptivity, luminal fluid homeostasis and blastocyst implantation
Scientific reports, 2016Co-Authors: Andrew M. Kelleher, Gregory W. Burns, Susanta K. Behura, Thomas E SpencerAbstract:Uterine Glands are essential for pregnancy in mice and likely humans, because they secrete or transport bioactive substances that regulate Uterine receptivity for blastocyst implantation. In mice, the uterus becomes receptive to blastocyst implantation on day 4, but is refractory by day 5. Here, blastocysts could be recovered from progesterone-induced Uterine Gland (PUGKO) but not wildtype (WT) mice on day 5 post-mating. Anti-adhesive Muc1 protein and microvilli were present on the luminal epithelium of PUGKO but not WT uteri. A number of known Uterine receptivity genes and Gland-specific genes were altered in the PUGKO uterus. Next, the uterus and Uterine luminal fluid (ULF) were obtained from WT and PUGKO mice on day 3, 4 and 5. Transcriptome analysis revealed that 580 genes were decreased in the PUGKO uterus, however ULF secrotome analysis revealed that many proteins and several amino acids were increased in the PUGKO ULF. Of note, many proteins encoded by many Gland-specific genes were not identified in the ULF of WT mice. These results support the ideas that Uterine Glands secrete factors that regulate ULF homeostasis and interact with other cell types in the uterus to influence Uterine receptivity and blastocyst implantation for the establishment of pregnancy.
