Nakajima, T., Iguchi, T., & Sato, T. (2016). Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1608808113
Nakajima T, Iguchi T, Sato T. Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct. Proceedings of the National Academy of Sciences of the United States of America. 2016. doi:10.1073/pnas.1608808113
Nakajima, T., et al. "Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct." Proceedings of the National Academy of Sciences of the United States of America, 2016.
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RRM Academy Synopsis
Retinoic acid signaling sets uterine and vaginal fate in fetal mice
Lab work on mouse tissue found that retinoic acid signaling decides the fate of fetal tissue that forms the uterus and vagina. In cultured Müllerian ducts, added retinoic acid made uterus-like lining. Blocking its receptors in those ducts made vagina-like lining.
Key Findings
Enzymes that make retinoic acid and endogenous retinoic acid activity were highest in the stroma of the proximal Müllerian duct and gradually decreased toward the caudal region in fetal mice.
In cultured Müllerian ducts at embryonic day 17.5, retinaldehyde or retinoic acid turned caudal epithelium into uterus-like simple columnar epithelium, negative for the vaginal markers TRP63 and KRT14.
Blocking retinoic acid receptors with a pan-RAR antagonist induced vagina-like stratified epithelium in middle Müllerian ducts, and cotreatment with retinoic acid canceled that effect.
Cultured ducts from embryonic day 14.5 or 17.5, treated and grafted under the kidney capsule of host mice, kept their induced uterus-like or vagina-like epithelium 30 days later, irrespective of estradiol.
Retinoic acid slightly raised Hoxa10 expression in cultured ducts at embryonic day 14.5, yet retinoic acid receptors did not bind the Hoxa10 promoter region examined.
Interpretation
The work is basic developmental biology in mice. Researchers grew fetal reproductive tract tissue in culture, grafted it into host mice, and used a reporter mouse to see where retinoic acid is active. The study used only mouse tissue. The authors state that no marker gene for stromal differentiation has been identified, so they took stroma-induced epithelial markers as the indication of it.
RRM Context
Retinoic acid comes from vitamin A. The authors recall that rat fetuses from mothers fed vitamin A-deficient diets had absent or incomplete Müllerian ducts. Restorative reproductive medicine looks for the cause of reproductive problems. A map of how the uterus and vagina form adds to that picture.
Our editorial summary of this paper, not the article's abstract.
Abstract
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.
