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

2020 ◽  
Vol 27 (12) ◽  
pp. 3307-3320
Author(s):  
Jumpei Terakawa ◽  
Vanida A. Serna ◽  
Devi M. Nair ◽  
Shigeru Sato ◽  
Kiyoshi Kawakami ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Reproductive Tract ◽  
Critical Role ◽  
Activin A ◽  
Genetically Engineered ◽  
Mitogen Activated Protein Kinase ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Duct Epithelium

AbstractDuring female mammal reproductive tract development, epithelial cells of the lower Müllerian duct are committed to become stratified squamous epithelium of the 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 the developing mouse reproductive tract, SIX1 expression was restricted to MDE within 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 the vaginal fornix. Using a mouse model of diethylstilbestrol (DES)-associated vaginal adenosis, we found DES action through epithelial estrogen receptor α (ESR1) inhibits activation of ΔNp63 locus in MDE by transcriptionally repressing SIX1 and RUNX1 in the vaginal fornix.

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 Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium

2013 ◽  
Vol 381 (1) ◽  
pp. 5-16 ◽  
Author(s):  
Monica M. Laronda ◽  
Kenji Unno ◽  
Kazutomo Ishi ◽  
Vanida A. Serna ◽  
Lindsey M. Butler ◽  
...  
Keyword(s):  
Cell Fate ◽  
Mullerian Duct ◽  
Cell Fate Decision ◽  
Müllerian Duct ◽  
Duct Epithelium ◽  
Fate Decision

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 Lhx1 is required in Müllerian duct epithelium for uterine development

2014 ◽  
Vol 389 (2) ◽  
pp. 124-136 ◽  
Author(s):  
Cheng-Chiu Huang ◽  
Grant D. Orvis ◽  
Kin Ming Kwan ◽  
Richard R. Behringer
Keyword(s):  
Mullerian Duct ◽  
Müllerian Duct ◽  
Duct Epithelium ◽  
Uterine Development

scholarly journals Estrogen Receptor 1 (ESR1; ERα), not ESR2 (ERβ), Modulates Estrogen-Induced Sex Reversal in the American Alligator, a Species With Temperature-Dependent Sex Determination

Endocrinology ◽  
2015 ◽  
Vol 156 (5) ◽  
pp. 1887-1899 ◽  
Author(s):  
Satomi Kohno ◽  
Melissa C. Bernhard ◽  
Yoshinao Katsu ◽  
Jianguo Zhu ◽  
Teresa A. Bryan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Sex Determination ◽  
Critical Role ◽  
Sex Reversal ◽  
Sensitive Period ◽  
Mullerian Duct ◽  
American Alligator ◽  
Temperature Dependent ◽  
Müllerian Duct

All crocodilians and many turtles exhibit temperature-dependent sex determination where the temperature of the incubated egg, during a thermo-sensitive period (TSP), determines the sex of the offspring. Estrogens play a critical role in sex determination in crocodilians and turtles, as it likely does in most nonmammalian vertebrates. Indeed, administration of estrogens during the TSP induces male to female sex reversal at a male-producing temperature (MPT). However, it is not clear how estrogens override the influence of temperature during sex determination in these species. Most vertebrates have 2 forms of nuclear estrogen receptor (ESR): ESR1 (ERα) and ESR2 (ERβ). However, there is no direct evidence concerning which ESR is involved in sex determination, because a specific agonist or antagonist for each ESR has not been tested in nonmammalian species. We identified specific pharmaceutical agonists for each ESR using an in vitro transactivation assay employing American alligator ESR1 and ESR2; these were 4,4′,4′’-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (WAY 200070), respectively. Alligator eggs were exposed to PPT or WAY 200070 at a MPT just before the TSP, and their sex was examined at the last stage of embryonic development. Estradiol-17β and PPT, but not WAY 200070, induced sex reversal at a MPT. PPT-exposed embryos exposed to the highest dose (5.0 μg/g egg weight) exhibited enlargement and advanced differentiation of the Müllerian duct. These results indicate that ESR1 is likely the principal ESR involved in sex reversal as well as embryonic Müllerian duct survival and growth in American alligators.

Timing and irreversibility of Müllerian duct inhibition in the embryonic reproductive tract of the human male

1984 ◽  
Vol 106 (2) ◽  
pp. 394-398 ◽  
Author(s):  
Osamu Taguchi ◽  
Gerald R. Cunha ◽  
W.Dwayne Lawrence ◽  
Stanley J. Robboy
Keyword(s):  
Reproductive Tract ◽  
Mullerian Duct ◽  
Müllerian Duct ◽  
Human Male

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 The regulation of ATF3 gene expression by mitogen-activated protein kinases

2006 ◽  
Vol 401 (2) ◽  
pp. 559-567 ◽  
Author(s):  
Dan Lu ◽  
Jingchun Chen ◽  
Tsonwin Hai
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Critical Role ◽  
Ectopic Expression ◽  
Signalling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Stress Signals ◽  
P38 Pathway

ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an ‘adaptive response’ gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.

scholarly journals The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors

2020 ◽  
Vol 295 (7) ◽  
pp. 1879-1888
Author(s):  
Chengfu Zhang ◽  
Hao Huang ◽  
Zhen Chen ◽  
Zunyi Zhang ◽  
Wenwen Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Fate ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Structural Domains ◽  
Histone Deacetylase 1 ◽  
Terminal Domain ◽  
Transcriptional Corepressors

The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.

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