ArticleDevelopmental biology2013
Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Müllerian duct epithelium.
Article in Developmental biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 61 citations in OpenAlex.
- Segmental specification of the human female fetal reproductive tract revealed by spatiotemporal dynamics.Nature cell biology · 2026Article
- A transient epithelial plasticity state defines the developmental window for uterine gland specification.bioRxiv : the preprint server for biology · 2026Article
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- Establishing the baseline: understanding follicle activation morphometrics in multiple mammalian species†.Biology of reproduction · 2025Article
- Uterine organoids reveal insights into epithelial specification and plasticity in development and disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Decoding Müllerian Duct Epithelial Regionalization.Molecular reproduction and development · 2025Review
- Complex and variable regulation of ΔNp63 and TAp63 by TGFβ has implications for the dynamics of squamous cell epithelial to mesenchymal transition.Scientific reports · 2024Article
- Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives.Toxics · 2023Review
- Estrogen receptor alpha regulates uterine epithelial lineage specification and homeostasis.iScience · 2023Article
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- Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma.Cancer science · 2022Article
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- Menstural function preservation treatment of a primary vaginal clear cell carcinoma with ovarian transposition and vaginal brachytherapy.Gynecologic oncology reports · 2021Article
- Mechanistic Drivers of Müllerian Duct Development and Differentiation Into the Oviduct.Frontiers in cell and developmental biology · 2021Review
- SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium.Cell death and differentiation · 2020Article
- Transcriptional landscape of the embryonic chicken Müllerian duct.BMC genomics · 2020Article
- Causal Evidence and Dispositions in Medicine and Public Health.International journal of environmental research and public health · 2020Article
- Proteomic analyses of decellularized porcine ovaries identified new matrisome proteins and spatial differences across and within ovarian compartments.Scientific reports · 2019Article
- Telomere dysfunction impairs epidermal stem cell specification and differentiation by disrupting BMP/pSmad/P63 signaling.PLoS genetics · 2019Article
- Environmental toxins and the impact of other endocrine disrupting chemicals in women's reproductive health.JBRA assisted reproduction · 2019Review
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11 authors at 5 institutions in 1 country.
Funding
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 Müllerian 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.
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