scholarly journals Osterix functions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression

2017 ◽  
Author(s):  
Rachel D. Mullen ◽  
Ying Wang ◽  
Bin Liu ◽  
Emma L. Moore ◽  
Richard R. Behringer
Keyword(s):  
Transforming Growth Factor Beta ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Mesenchymal Cells ◽  
Female Reproductive Tract ◽  
Mullerian Duct ◽  
Male And Female ◽  
Müllerian Duct

AbstractIn mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Müllerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme-epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct and upper vagina. It is well established that transforming growth factor-beta family member anti-Müllerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 receptors expressed in MD mesenchyme regulate MD regression. However, little is known about the molecular network regulating downstream actions of AMH signaling. To identify potential AMH-induced genes and regulatory networks controlling MD regression in a global non-biased manner, we examined transcriptome differences in MD mesenchyme between males (AMH signaling on) and females (AMH signaling off) by RNA-Seq analysis of purified fetal MD mesenchymal cells. This analysis found 82 genes up-regulated in males during MD regression and identified Osterix (Osx)/Sp7, a key transcriptional regulator of osteoblast differentiation and bone formation, as a novel downstream effector of AMH signaling during MD regression. Osx/OSX was expressed in a male-specific pattern in MD mesenchyme during MD regression. OSX expression was lost in mutant males without AMH signaling. In addition, transgenic mice ectopically expressing human AMH in females induced a male pattern of Osx expression. Together these results indicate that AMH signaling is necessary and sufficient for Osx expression in the MD mesenchyme. In addition, MD regression was delayed in Osx null males, identifying Osx as a new factor that regulates MD regression.SignificanceIn mammals, each embryo forms both male and female reproductive tract organ progenitor tissues. Anti-Müllerian hormone (AMH) secreted by fetal testes acts on mesenchyme cells adjacent to the Müllerian duct (MD) epithelium, the progenitor tissue of the female reproductive tract, to induce MD regression. While AMH and early AMH signaling components are elucidated, downstream gene networks directing this process are largely unknown. A global non-biased approach using whole transcriptome sequencing of fetal MD mesenchymal cells identified 82 factors as potential target genes of AMH including Osterix (Osx). Our findings provide in vivo evidence Osx is an AMH-induced gene that regulates MD regression. Identification of Osx may provide key insights into gene regulatory networks underlying MD regression and male sex differentiation.

scholarly journals A gene regulatory network for Müllerian duct regression

2019 ◽  
Vol 5 (3) ◽  
Author(s):  
Malcolm M Moses ◽  
Richard R Behringer
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Reproductive Tract ◽  
Sex Differentiation ◽  
Female Reproductive Tract ◽  
Mullerian Duct ◽  
Male And Female ◽  
Müllerian Duct ◽  
New Genes ◽  
Gene Regulatory

Abstract Mammalian embryos initially develop progenitor tissues for both male and female reproductive tract organs, known as the Wolffian ducts and the Müllerian ducts, respectively. Ultimately, each individual develops a single set of male or female reproductive tract organs. Therefore, an essential step for sex differentiation is the regression of one duct and growth and differentiation of the other duct. In males, this requires Müllerian duct regression and Wolffian duct growth and differentiation. Müllerian duct regression is induced by the expression of Amh, encoding anti-Müllerian hormone, from the fetal testes. Subsequently, receptor-mediated signal transduction in mesenchymal cells surrounding the Müllerian duct epithelium leads to duct elimination. The genes that induce Amh transcription and the downstream signaling that results from Amh activity form a pathway. However, the molecular details of this pathway are currently unknown. A set of essential genes for AMH pathway function has been identified. More recently, transcriptome analysis of male and female Müllerian duct mesenchyme at an initial stage of regression has identified new genes that may mediate elimination of the Müllerian system. The evidence taken together can be used to generate an initial gene regulatory network describing the Amh pathway for Müllerian duct regression. An Amh gene regulatory network will be a useful tool to study Müllerian duct regression, sex differentiation, and its relationship to environmental influences.

scholarly journals Osterix functions downstream of anti-Müllerian hormone signaling to regulate Müllerian duct regression

2018 ◽  
Vol 115 (33) ◽  
pp. 8382-8387 ◽  
Author(s):  
Rachel D. Mullen ◽  
Ying Wang ◽  
Bin Liu ◽  
Emma L. Moore ◽  
Richard R. Behringer
Keyword(s):  
Regulatory Networks ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Specific Pattern ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Downstream Effector ◽  
Male Specific ◽  
Necessary And Sufficient

In mammals, the developing reproductive tract primordium of male and female fetuses consists of the Wolffian duct and the Müllerian duct (MD), two epithelial tube pairs surrounded by mesenchyme. During male development, mesenchyme–epithelia interactions mediate MD regression to prevent its development into a uterus, oviduct, and upper vagina. It is well established that transforming growth factor-β family member anti-Müllerian hormone (AMH) secreted from the fetal testis and its type 1 and 2 receptors expressed in MD mesenchyme regulate MD regression. However, little is known about the molecular network regulating downstream actions of AMH signaling. To identify potential AMH-induced genes and regulatory networks controlling MD regression in a global nonbiased manner, we examined transcriptome differences in MD mesenchyme between males (AMH signaling on) and females (AMH signaling off) by RNA-seq analysis of purified fetal MD mesenchymal cells. This analysis found 82 genes up-regulated in males during MD regression and identified Osterix (Osx)/Sp7, a key transcriptional regulator of osteoblast differentiation and bone formation, as a downstream effector of AMH signaling during MD regression. Osx/OSX was expressed in a male-specific pattern in MD mesenchyme during MD regression. OSX expression was lost in mutant males without AMH signaling. In addition, transgenic mice ectopically expressing human AMH in females induced a male pattern of Osx expression. Together, these results indicate that AMH signaling is necessary and sufficient for Osx expression in the MD mesenchyme. In addition, MD regression was delayed in Osx-null males, identifying Osx as a factor that regulates MD regression.

scholarly journals SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium

2018 ◽  
Author(s):  
Jumpei Terakawa ◽  
Vanida A. Serna ◽  
Devi Nair ◽  
Shigeru Sato ◽  
Kiyoshi Kawakami ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Reproductive Tract ◽  
Mesenchymal Cells ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Duct Epithelium ◽  
Putative Precursor

AbstractDuring female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of vagina and ectocervix, when the expression of ΔNp63 transcription factor is induced by mesenchymal cells. The absence of ΔNp63 expression leads to adenosis, the putative precursor of vaginal adenocarcinoma. Our previous studies with genetically engineered mouse models have established that fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK), bone morphogenetic protein (BMP)/SMAD, and activin A/runt related transcription factor 1 (RUNX1) signaling pathways are independently required for ΔNp63 expression in Müllerian duct epithelium (MDE). Here we report that sine oculis homeobox homolog 1 (SIX1) plays a critical role in the activation of ΔNp63 locus in MDE as a downstream transcription factor of mesenchymal signals. In mouse developing reproductive tract, SIX1 expression was restricted to MDE of the future cervix and vagina. SIX1 expression was totally absent in SMAD4 null MDE and was reduced in RUNX1 null and FGFR2 null MDE, indicating that SIX1 is under the control of vaginal mesenchymal factors, BMP4, activin A and FGF7/10. Furthermore, Six1, Runx1 and Smad4 gene-dose-dependently activated ΔNp63 expression in MDE within vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) down-regulates SIX1 and RUNX1 in MDE within the vaginal fornix. This study establishes that the vaginal/ectocervical cell fate of MDE is regulated by a collaboration of multiple transcription factors including SMAD4, SIX1 and RUNX1, and the down-regulation of these key transcription factors leads to vaginal adenosis.Author SummaryIn embryogenesis, differentiation fate of cells is specified through constant communication between neighboring cells. In this study, we investigated the molecular mechanism of epithelial cell fate commitment in the lower female reproductive organs utilizing mouse genetic models. The cell fate of epithelial cells in the uterus, cervix and vagina is directed by signaling from mesenchymal cells. We demonstrated that within the epithelial cells of the developing vagina, signals from mesenchymal cells are integrated into activities of transcription factors including SMAD4, RUNX1 and SIX1, which dose-dependently co-operate in the determination of vaginal epithelial cell fate. Disruption of these processes alters the cell fate from vaginal to uterine epithelium, resulting in a condition called vaginal adenosis, a putative precursor of vaginal adenocarcinoma. Women exposed to diethylstilbestrol (DES) in the womb have about 40 times the risk of developing vaginal adenocarcinoma. We determined that developmental exposure to DES induces vaginal adenosis by repressing SIX1 and RUNX1 through ESR1 in the epithelial cells. This discovery enhances the understanding of how early-life events, such as exposure to endocrine disruptors, causes vaginal adenosis, and thus may contribute to the prevention and therapeutic treatment of idiopathic vaginal adenocarcinoma.

scholarly journals Wnt4 coordinates directional cell migration and extension of the Müllerian duct essential for ontogenesis of the female reproductive tract

2015 ◽  
Vol 25 (6) ◽  
pp. 1059-1073 ◽  
Author(s):  
Renata Prunskaite-Hyyryläinen ◽  
Ilya Skovorodkin ◽  
Qi Xu ◽  
Ilkka Miinalainen ◽  
Jingdong Shan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Directional Cell Migration

scholarly journals Expansion of CD16-Negative Natural Killer Cells in the Peripheral Blood of Patients with Metastatic Melanoma

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Shernan G. Holtan ◽  
Douglas J. Creedon ◽  
Michael A. Thompson ◽  
Wendy K. Nevala ◽  
Svetomir N. Markovic
Keyword(s):  
Nk Cells ◽  
Metastatic Melanoma ◽  
Natural Killer ◽  
Transforming Growth Factor Beta ◽  
Peripheral Blood ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Nk Cell ◽  
Female Reproductive Tract

Altered natural killer (NK) cell function is a component of the global immune dysregulation that occurs in advanced malignancies. Another condition associated with altered NK homeostasis is normal pregnancy, where robust infiltration with CD16− CD9+ NK cells can be identified in decidual tissues, along with a concomitant expansion of CD16− NK cells in the maternal peripheral blood. In metastatic melanoma, we identified a similar expansion of peripheral blood CD16− NK cells (median 7.4% in 41 patients with melanoma compared with 3.0% in 29 controls,P<.001). A subset of NK cells in melanoma patients also expresses CD9, which is characteristically expressed only on NK cells within the female reproductive tract. Expansion of CD16− NK cells was associated with elevated plasma transforming growth factor-beta (TGF-βlevels (median 20 ng/ml, Spearman'sρ=0.81,P=.015)). These findings suggest the possibility of exploring anti-TGF-βtherapy to restore NK function in melanoma.

scholarly journals YAP and TAZ are required for the postnatal development and the maintenance of the structural integrity of the oviduct

Reproduction ◽  
2020 ◽  
Vol 160 (2) ◽  
pp. 307-318
Author(s):  
Philippe Godin ◽  
Mayra Tsoi ◽  
Marilène Paquet ◽  
Derek Boerboom
Keyword(s):  
Postnatal Development ◽  
Reproductive Tract ◽  
Structural Integrity ◽  
Hippo Pathway ◽  
Female Reproductive Tract ◽  
Mullerian Duct ◽  
Developmental Defects ◽  
Müllerian Duct ◽  
And Function ◽  
The Hippo Pathway

The development of the Müllerian ducts into the female reproductive tract requires the coordination of multiple signaling pathways that regulate proliferation, apoptosis and differentiation. The Hippo pathway has been reported to interact with several pathways with established roles in Müllerian duct development; yet, its potential roles in reproductive tract development and function remain mostly uncharacterized. The objective of this study was therefore to characterize the roles of the Hippo transcriptional coactivators YAP and TAZ in the female reproductive tract using transgenic mouse models. This report shows that the concomitant conditional inactivation of Yap and Taz in the mouse Müllerian duct mesenchyme results in postnatal developmental defects of the oviduct. Most notably, discontinuities in the myosalpinx layer lead to the progressive formation of cystic dilations of the isthmus. These defects prevented embryo transport and subsequent implantation in older animals, causing infertility. The loss of YAP/TAZ did not appear to affect other biological processes known to be required for the maintenance of oviductal wall integrity, such as TGF-β/SMAD and Notch signaling and the biogenesis of miRNA, suggesting that the Hippo pathway acts independently of these processes to direct oviduct development. Taken together, these results suggest redundant and essential roles for YAP and TAZ in the postnatal development of the oviduct and the maintenance of its structural integrity.

Various Müllerian-duct anomalies in Women at Rural Tertiary Care Center of Northern India: An Observational Study

2021 ◽  
Vol 17 ◽  
Author(s):  
Naina Kumar ◽  
Ashu Yadav
Keyword(s):  
Observational Study ◽  
Rural Women ◽  
Female Reproductive Tract ◽  
Mullerian Duct ◽  
Mullerian Anomalies ◽  
Müllerian Duct ◽  
Müllerian Anomalies ◽  
Northern India ◽  
Müllerian Duct Anomalies ◽  
Mullerian Duct Anomalies

Aims: Present study was conducted to know presentations and nature of Müllerian-duct anomalies in rural women. Background: Müllerian anomalies are congenital defects of female reproductive tract resulting from faulty development and fusion of Müllerian ducts. Objectives: To identify common Müllerian anomalies, their presentation, radiological appearances, complications, associated renal anomalies in rural women of Northern India. Methods: Present observational study was conducted on 181 female patients with suspected Müllerian anomalies presenting to the outpatient department of Obstetrics and Gynecology with various complaints. Data included age, religion, menarche, previous pregnancy if any, duration of infertility, presenting complaints, type of Müllerian anomaly, incidental or symptomatic, diagnostic method, associated anomalies. Statistical analysis was done using SPSS 22.0 version software. Results: Of 181 patients, 16.5% were adolescents, 83.5% adult women with an overall mean (SD) age of 25.02 (5.96) years. Of these, 170 had true Müllerian-duct anomalies and 11 had defects other than Müllerian anomalies, hence excluded. Total 158(92.9%) patients were symptomatic and 12(7.1%) asymptomatic at presentation. The majority (75.9%) were diagnosed incidentally during their visit to the department for various complaints of which infertility (32.4%) was most common. Septate uterus (29.4%) was most common anomaly diagnosed followed by Müllerian agenesis/hypoplasia (22.9%). Around 11.2% cases had associated renal and collecting system anomalies with unilateral renal agenesis (47.4%) being most common. Conclusion: Hence, Müllerian-duct anomalies have diverse presentations and most of them are diagnosed incidentally. Other: The exact prevalence of Müllerian-duct anomalies may be high, especially in rural India due to lack of knowledge and societal pressures.

scholarly journals Semen Modulates Inflammation and Angiogenesis in the Reproductive Tract of Female Rabbits

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2207
Author(s):  
Jaume Gardela ◽  
Amaia Jauregi-Miguel ◽  
Cristina A. Martinez ◽  
Heriberto Rodríguez-Martinez ◽  
Manel López-Béjar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Reproductive Tract ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Breeding Systems ◽  
Preimplantation Embryos ◽  
Natural Mating ◽  
Anti Inflammatory

The maternal environment modulates immune responses to facilitate embryo development and ensure pregnancy. Unraveling this modulation could improve the livestock breeding systems. Here it is hypothesized that the exposure of the female rabbit reproductive tract to semen, as well as to early embryos, modulates inflammation and angiogenesis among different tissue segments. qPCR analysis of the gene expression changes of the anti-inflammatory interleukin-10 (IL10) and transforming growth factor beta family (TGFβ1–3) and the angiogenesis mediator vascular endothelial growth factor (VEGF-A) were examined in response to mating or insemination with sperm-free seminal plasma (SP). Reproductive tract segment (cervix to infundibulum) samples were obtained in Experiment 1, 20 h after gonadotropin-releasing hormone (GnRH) stimulation (control), natural mating (NM) or vaginal infusion with sperm-free SP (SP-AI). Additionally, segmented samples were also obtained at 10, 24, 36, 68 or 72 h after GnRH-stimulation and natural mating (Experiment 2). The results of gene expression, analyzed by quantitative PCR, showed that NM effects were mainly localized in the uterine tissues, depicting clear temporal variation, while SP-AI effects were restricted to the oviduct. Changes in anti-inflammatory and angiogenesis mediators indicate an early response in the uterus and a late modulation in the oviduct either induced by semen or preimplantation embryos. This knowledge could be used in the implementation of physiological strategies in breeding systems to face the new challenges on rabbit productivity and sustainability.

scholarly journals Do spermathecal morphology and inter-mating interval influence paternity in the polyandrous beetle Tribolium castaneum?

Behaviour ◽  
2006 ◽  
Vol 143 (5) ◽  
pp. 643-658 ◽  
Author(s):  
Ludovic Arnaud ◽  
Giorgina Bernasconi ◽  
Yves Brostaux ◽  
Eric P. Meyer
Keyword(s):  
Sperm Competition ◽  
Tribolium Castaneum ◽  
Reproductive Tract ◽  
Sperm Storage ◽  
Female Reproductive Tract ◽  
Phenotypic Marker ◽  
Male And Female ◽  
The Difference ◽  
Different Strains

AbstractIn polyandrous insects, postcopulatory sexual selection is a pervasive evolutionary force favouring male and female traits that allow control of offspring paternity. Males may influence paternity through adaptations for sperm competition, and females through adaptations facilitating cryptic female choice. Yet, the mechanisms are often complex, involving behaviour, physiology or morphology, and they are difficult to identify. In red flour beetles (Tribolium castaneum), paternity varies widely, and evidence suggests that both male and female traits influence the outcome of sperm competition. To test the role of spermathecal morphology and of sperm storage processes on the outcome of sperm competition, we mated each of 26 virgin females with two males, one of which carrying a phenotypic marker to assign offspring paternity. We manipulated the interval between mating with the first and the second male, to create different conditions of sperm storage (overlapping and non-overlapping) in the female reproductive tract. To investigate the role of sperm storage more closely, we examined the relationship between paternity and spermathecal morphology in a subset of 14 experimental females. In addition, we also characterized variation in spermathecal morphology in three different strains, wildtype, Chicago black and Reindeer. No significant influence of the intermating interval was found on the paternity of the focal male, although the direction of the difference was in the expected direction of higher last male paternity for longer intervals. Moreover, paternity was not significantly associated with spermathecal morphology, although spermathecal volume, complexity, and tubule width varied significantly and substantially among individuals in all investigated strains.

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