The Experts below are selected from a list of 846 Experts worldwide ranked by ideXlab platform

Takeshi Kurita - One of the best experts on this subject based on the ideXlab platform.

  • six1 cooperates with runx1 and smad4 in cell fate commitment of mullerian duct epithelium
    Cell Death & Differentiation, 2020
    Co-Authors: Jumpei Terakawa, Vanida A Serna, Devi M Nair, Shigeru Sato, Kiyoshi Kawakami, Sally Radovick, Pascal Maire, Takeshi Kurita
    Abstract:

    During female mammal reproductive tract development, epithelial cells of the lower Mullerian 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 Mullerian 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.

  • SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium
    2018
    Co-Authors: Jumpei Terakawa, Vanida A Serna, Devi M Nair, Shigeru Sato, Kiyoshi Kawakami, Sally Radovick, Pascal Maire, Takeshi Kurita
    Abstract:

    During female mammal reproductive tract development, epithelial cells of the lower Mullerian 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 Mullerian 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.

  • the development of cervical and vaginal Adenosis as a result of diethylstilbestrol exposure in utero
    Differentiation, 2012
    Co-Authors: Monica M Laronda, Kenji Unno, Lindsey M Butler, Takeshi Kurita
    Abstract:

    Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Mullerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces Adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.

  • roles of p63 in the diethylstilbestrol induced cervicovaginal Adenosis
    Development, 2004
    Co-Authors: Takeshi Kurita, Alea A Mills, Gerald R Cunha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal Adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Mullerian duct epithelium. The cell fate of Mullerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Mullerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Mullerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day I to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as Adenosis.

Monica M Laronda - One of the best experts on this subject based on the ideXlab platform.

  • diethylstilbestrol induces vaginal Adenosis by disrupting smad runx1 mediated cell fate decision in the mullerian duct epithelium
    Developmental Biology, 2013
    Co-Authors: Monica M Laronda, Vanida A Serna, Alea A Mills, Kenji Unno, Lindsey M Butler, Kazutomo Ishi, Grant D Orvis, Richard R Behringer, Chuxia Deng, Satrajit Sinha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal Adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal Adenosis remains elusive. Here we report that DES induces vaginal Adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Mullerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed Adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced Adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated Adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal Adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

  • the development of cervical and vaginal Adenosis as a result of diethylstilbestrol exposure in utero
    Differentiation, 2012
    Co-Authors: Monica M Laronda, Kenji Unno, Lindsey M Butler, Takeshi Kurita
    Abstract:

    Exposure to exogenous hormones during development can result in permanent health problems. In utero exposure to diethylstilbestrol (DES) is probably the most well documented case in human history. DES, an orally active synthetic estrogen, was believed to prevent adverse pregnancy outcome and thus was routinely given to selected pregnant women from the 1940s to the 1960s. It has been estimated that 5 million pregnant women worldwide were prescribed DES during this period. In the early 1970s, vaginal clear cell adenocarcinomas (CCACs) were diagnosed in daughters whose mother took DES during pregnancy (known as DES daughters). Follow-up studies demonstrated that exposure to DES in utero causes a spectrum of congenital anomalies in female reproductive tracts and CCACs. Among those, cervical and vaginal adenoses are most commonly found, which are believed to be the precursors of CCACs. Transformation related protein 63 (TRP63/p63) marks the cell fate decision of Mullerian duct epithelium (MDE) to become squamous epithelium in the cervix and vagina. DES disrupts the TRP63 expression in mice and induces Adenosis lesions in the cervix and vagina. This review describes mouse models that can be used to study the development of DES-induced anomalies, focusing on cervical and vaginal adenoses, and discusses their molecular pathogenesis.

Satrajit Sinha - One of the best experts on this subject based on the ideXlab platform.

  • diethylstilbestrol induces vaginal Adenosis by disrupting smad runx1 mediated cell fate decision in the mullerian duct epithelium
    Developmental Biology, 2013
    Co-Authors: Monica M Laronda, Vanida A Serna, Alea A Mills, Kenji Unno, Lindsey M Butler, Kazutomo Ishi, Grant D Orvis, Richard R Behringer, Chuxia Deng, Satrajit Sinha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal Adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal Adenosis remains elusive. Here we report that DES induces vaginal Adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Mullerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed Adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced Adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated Adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal Adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

Vanida A Serna - One of the best experts on this subject based on the ideXlab platform.

  • six1 cooperates with runx1 and smad4 in cell fate commitment of mullerian duct epithelium
    Cell Death & Differentiation, 2020
    Co-Authors: Jumpei Terakawa, Vanida A Serna, Devi M Nair, Shigeru Sato, Kiyoshi Kawakami, Sally Radovick, Pascal Maire, Takeshi Kurita
    Abstract:

    During female mammal reproductive tract development, epithelial cells of the lower Mullerian 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 Mullerian 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.

  • SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium
    2018
    Co-Authors: Jumpei Terakawa, Vanida A Serna, Devi M Nair, Shigeru Sato, Kiyoshi Kawakami, Sally Radovick, Pascal Maire, Takeshi Kurita
    Abstract:

    During female mammal reproductive tract development, epithelial cells of the lower Mullerian 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 Mullerian 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.

  • diethylstilbestrol induces vaginal Adenosis by disrupting smad runx1 mediated cell fate decision in the mullerian duct epithelium
    Developmental Biology, 2013
    Co-Authors: Monica M Laronda, Vanida A Serna, Alea A Mills, Kenji Unno, Lindsey M Butler, Kazutomo Ishi, Grant D Orvis, Richard R Behringer, Chuxia Deng, Satrajit Sinha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal Adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal Adenosis remains elusive. Here we report that DES induces vaginal Adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Mullerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed Adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced Adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated Adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal Adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

Alea A Mills - One of the best experts on this subject based on the ideXlab platform.

  • diethylstilbestrol induces vaginal Adenosis by disrupting smad runx1 mediated cell fate decision in the mullerian duct epithelium
    Developmental Biology, 2013
    Co-Authors: Monica M Laronda, Vanida A Serna, Alea A Mills, Kenji Unno, Lindsey M Butler, Kazutomo Ishi, Grant D Orvis, Richard R Behringer, Chuxia Deng, Satrajit Sinha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero frequently develop vaginal Adenosis, from which clear cell adenocarcinoma can arise. Despite decades of extensive investigation, the molecular pathogenesis of DES-associated vaginal Adenosis remains elusive. Here we report that DES induces vaginal Adenosis by inhibiting the BMP4/Activin A-regulated vaginal cell fate decision through a downregulation of RUNX1. BMP4 and Activin A produced by vaginal mesenchyme synergistically activated the expression of ΔNp63, thus deciding vaginal epithelial cell fate in the Mullerian duct epithelial cells (MDECs) via direct binding of SMADs on the highly conserved 5′ sequence of ΔNp63. Therefore, mice in which Smad4 was deleted in MDECs failed to express ΔNp63 in vaginal epithelium and developed Adenosis. This SMAD-dependent ΔNp63 activation required RUNX1, a binding partner of SMADs. Conditional deletion of Runx1 in the MDECs induced Adenosis in the cranial portion of vagina, which mimicked the effect of developmental DES-exposure. Furthermore, neonatal DES exposure downregulated RUNX1 in the fornix of the vagina, where DES-associated Adenosis is frequently found. This observation strongly suggests that the downregulation of RUNX1 is the cause of vaginal Adenosis. However, once cell fate was determined, the BMP/Activin-SMAD/RUNX1 signaling pathway became dispensable for the maintenance of ΔNp63 expression in vaginal epithelium. Instead, the activity of the ΔNp63 locus in vaginal epithelium was maintained by a ΔNp63-dependent mechanism. This is the first demonstration of a molecular mechanism through which developmental chemical exposure causes precancerous lesions by altering cell fate.

  • roles of p63 in the diethylstilbestrol induced cervicovaginal Adenosis
    Development, 2004
    Co-Authors: Takeshi Kurita, Alea A Mills, Gerald R Cunha
    Abstract:

    Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal Adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Mullerian duct epithelium. The cell fate of Mullerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Mullerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Mullerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day I to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as Adenosis.