Retinoic acid signaling determines the fate of the uterus from the mouse Müllerian duct

•RA is essential for the initiation and maintenance of Müllerian ductal development.•RA signaling establishes the border between uterus and vagina during development.•RA maintains epithelial homeostasis in adult uterus and vagina.•Chemicals disrupting RA signaling may adversely affect the female reproductive tract.•RA signaling may be important for prevention of adverse effects by EDCs. In female mice, the Müllerian duct develops into the oviduct, uterus and vagina. The fate of epithelia is determined by factors secreted from the mesenchyme. Retinoic acid (RA) and its receptors are present in the mesenchyme of cranial Müllerian duct. RA induces Müllerian duct to uterine epithelial differentiation whereas inhibition of RA receptors induces vaginal epithelial differentiation. Thus, RA signaling in the Müllerian duct is required to promote differentiation of the mesenchyme into the future uterus. Perinatal estrogen exposure induces various abnormalities in Müllerian duct-derived organs. These include a cranial shift of the border among oviduct, uterus and vagina as well as precancerous lesions suppressed by co-treatment with RA and estrogen. Since RA synthesis enzymes and receptors are expressed both in the epithelium and stroma after birth, RA signaling may act in the epithelia to maintain adult epithelial homeostasis and to prevent irreversible lesions induced by perinatal estrogen exposure.