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

Laronda, Monica M.; Unno, Kenji; Ishi, K; Serna, Vanida A.; Butler, Lindsey M.; Mills, Alea A.; Orvis, Grant D.; Behringer, Richard R.; Deng, Chu‐Xia; Sinha, Satrajit; Kurita, Takeshi

doi:10.1016/j.ydbio.2013.06.024

Cited by 51 publications

(82 citation statements)

References 45 publications

(64 reference statements)

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“…The fate-determined stroma then secreted factors to induce their respective epithelia. In female mouse embryos, RA inhibits inhibin βA expression in the urogenital sinus (40), and activin A formed by the inhibin βA is important for vaginal epithelial differentiation (7,8). These data support a model in which key factors regulated by RA-RAR signaling can play critical roles in fate determination in epithelium and stroma of the female reproductive tracts.…”

Section: Discussionsupporting

confidence: 63%

“…Data from these studies indicate that factors secreted from the stroma determine the fate, differentiation, and growth of the overlying epithelia into the oviduct, uterus, and vagina of developing mice. The epithelial fate-determining factors have been identified in the female reproductive tracts (4,(6)(7)(8)(9), and posterior Hoxa genes, which are differentially expressed along the A-P axis, are important for development of the female reproductive tracts (10); however, earlier steps in the stromal differentiation of the female reproductive tracts from the Müllerian ducts remain unclear.…”

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confidence: 99%

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Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

Nakajima

Iguchi

Satō

2016

Proc. Natl. Acad. Sci. U.S.A.

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The Müllerian duct develops into the oviduct, uterus, and vagina, all of which are quite distinct in their morphology and function. The epithelial fate of these female reproductive organs in developing mice is determined by factors secreted from the stroma; however, how stromal differentiation occurs in the female reproductive organs derived from the Müllerian duct is still unclear. In the present study, roles of retinoic acid (RA) signaling in developing female reproductive tracts were investigated. Retinol dehydrogenase 10 (RDH10) and aldehyde dehydrogenase family 1 subfamily A2 (ALDH1A2) mRNAs and proteins and transactivation activity of endogenous RA were found in the stroma of proximal Müllerian ducts and gradually decreased from the proximal to caudal regions in fetal mice. In organ-cultured Müllerian ducts, retinaldehyde or RA treatment induced uterine epithelial differentiation, defined as a layer of columnar epithelial cells negative for oviductal and vaginal epithelial markers. In contrast, inhibition of RA receptor (RAR) signaling induced vaginal epithelial differentiation, characterized as vaginal epithelial marker genes–positive stratified epithelium. Grafting experiments of the organ-cultured Müllerian duct revealed irreversible epithelial fate determination. Although RAR did not directly bind to the homeobox A10 (Hoxa10) promoter region, RA–RAR signaling stimulated Hoxa10 expression. Thus, RA–RAR signaling in the Müllerian duct determines the fate of stroma to form the future uterus and vagina.

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

Nakajima

Iguchi

Satō

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Immunohistochemistry may help in defining vaginal-cervical-uterine boundaries. Immunostaining for ISL1 is promising in discerning the vaginal/cervical boundary, as ISL1 is enriched in vaginal mesenchyme, but not uterine mesenchyme (Gene Expression Omnibus (GEO) Series GSE44697) (Laronda et al, 2013) and Kurita (unpublished). ISL immunostaining is prominent in the developing vagina’s mesenchyme (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, ΔNp63 expression in Müllerian epithelium is subsequently followed by expression of keratin 14 and other vaginal epithelial differentiation markers. Significantly, in Müllerian duct epithelium-specific ΔNp63 null mice the vaginal epithelium remains columnar and exhibits a variety of uterine epithelial differentiation markers (Kurita et al, 2000; Laronda et al, 2013). Such findings show that ΔNp63 is critical for vaginal differentiation of Müllerian epithelium (Kurita et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

New insights into human female reproductive tract development

Kurita²,

et al. 2017

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We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Müllerian epithelium and the lower 1/5th derived from urogenital sinus epithelium, while Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Müllerian ducts) cranially and squamous epithelium of urogenital sinus caudally. Since Müllerian and urogenital sinus epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer’s proposal that human vaginal epithelium derives solely from urogenital sinus epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.

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“…The development of vaginal adenocarcinoma by in utero exposure to diethylstilbestrol is the best-documented clinical cases of such transformation: diethylstilbestrol causes precancerous lesions by altering epithelial cell fate through disruption of cell-cell communication (40). Ovarian malignancies developed in Fancd2 and Dazl null mutant mice from altered micro and endocrine environments through premature oocyte loss (41).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors

et al. 2016

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Cell-cell interactions play crucial roles in the maintenance of tissue homeostasis, a loss of which often leads to varying diseases, including cancer. Here, we report that uncontrolled PI3K activity within oocytes irreversibly transforms granulosa cells (GC), causing GC tumors (GCT) through perturbed local cell-communication. Previously, we reported reproductive phenotypes of transgenic mice, in which expression of constitutively active mutant PI3K was induced in primordial oocytes by Gdf9-iCre. The transgenic mice (Cre+) demonstrated severe ovarian phenotypes, including the overgrowth of excess ovarian follicles and anovulation. Surprisingly, the Cre+ mice became cachectic by postnatal day 80 due to bilateral GCT. Although GCT cells proliferated independently of oocytes, local interactions with mutant PI3K-positive oocytes during early folliculogenesis were essential for the GC transformation. Growing GCT cells expressed high levels of inhibin βA and nuclear SMAD3, and the proliferation rate was positively correlated with a high activin A to inhibin A ratio. These results suggested that the tumor cells stimulated their growth through an activin A autocrine signaling pathway, a hypothesis confirmed by activin A secretion in cultured GCT cells which proliferated in response. Although communication between the oocyte and surrounding somatic cells is critical for the normal development of ovarian follicles, perturbations in oocyte-GC communication during early folliculogenesis can induce GCT by activating an autocrine growth circuit program in GC.

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

Cited by 51 publications

References 45 publications

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct

New insights into human female reproductive tract development

Constitutive Activation of PI3K in Oocyte Induces Ovarian Granulosa Cell Tumors

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