Retinoic acid signaling and uterine epithelial cell fate

The National Institute of Child Health and Human Development awarded The Washington University $427,625 on May 15, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate retinoic acid signaling and uterine epithelial cell fate determination.

The research examines how retinoic acid signaling maintains uterine epithelial cell identity during adult homeostasis and tests hypotheses about the antagonistic relationship between retinoic acid and estrogen signaling in regulating epithelial cell differentiation in the female reproductive tract. Two aims structure the investigation: Aim 1 addresses the cell-autonomous function of retinoic acid receptors in female reproductive tract development and adult maintenance, with additional aims examining stem and progenitor cell specification and the stromal signals required for cell fate maintenance.

Work is performed at The Washington University in University City, Missouri, with a period of performance from May 15, 2026, through May 31, 2028. The project is a Research Project Grant (R21) mechanism, which provides exploratory and developmental research funding.

Abstract

The mammalian female reproductive tract (FRT), consisting of the oviducts, uterus, cervix and vagina, is essential for pregnancy establishment and a frequent site of human disease, including infertility and cancer. The embryonic origin of FRT is the müllerian ducts, a pair of epithelial tubes with a surrounding mesenchyme. Once formed, the müllerian duct regionally divides into segments along the anterior- posterior axis with each segment developing into distinct structure (oviduct, uterus, cervix and upper vagina). Classical tissue recombination experiments have shown that the müllerian duct epithelial cell fate determination along the anterior-posterior axis is mediated by signals from the underlying stroma and retinoic acid (RA) signaling has been proposed to be the stromal CUE for uterine epithelial cell fate determination. Despite advances in the molecular understanding of MDE specification during FRT development, there remains a striking knowledge GAP in our understanding of how adult uterine cell fate is maintained. Recently a group of uterine epithelial cells at the intersection of luminal and glandular epithelium has been proposed to be a uterine stem cell population capable of differentiating into either luminal or glandular cells. However, little is known how these stem/progenitor cells acquire and maintain uterine cell fate and whether stromal signals are required for their specification. Our preliminary studies provide strong genetic data supporting the idea that RA signaling is continually required to maintain uterine epithelial cell fate during adult uterine homeostasis. In addition, our data suggest a model in which an antagonistic relationship between RA and estrogen signaling regulates müllerian duct epithelial cytodifferentiation. These hypotheses will be tested in two aims. Aim 1 will examine the cell-autonomous function of retinoic acid receptors in FRT development and in adult uterine cell fate determination. Aim 2 will test the hypothesis that an RA-estrogen antagonism drives FRT cell fate determination both in mouse and in human. Successful completion of these studies may provide novel insights into female infertility and uterine cancer as a result of signaling imbalance between RA and estrogen, which could have a long-lasting impact in multiple research fields including development, fertility and cancer research.