title: Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct.
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.
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan.|Department of Biological Science and Technology, Tokyo University of Science, Tokyo 125-8585, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan.|Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
authors.forename: Taisen
authors.initials: T
authors.lastname: Iguchi
authors.affiliation: Graduate School of Nanobioscience, Yokohama City University, Yokohama 236-0027, Japan; tomomi@yokohama-cu.ac.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sato
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009095:Mullerian Ducts / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D009924:Organ Culture Techniques; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D050697:Retinal Dehydrogenase; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism*; D014599:Uterus / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D014621:Vagina / Q000166:cytology / Q000196:embryology / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C088144:HoxA protein; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C113992:trans-retinol dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase
keywords: Müllerian duct; oviduct; retinoic acid; uterus; vagina