Decoding Müllerian Duct Epithelial Regionalization

Müllerian ducts (MD), also known as paramesonephric ducts, are the primordial anlage of the female reproductive tract organs including the oviduct, uterus, cervix and upper vagina along the craniocaudal axis. Although the general architecture of MD-derived organs is conserved, each organ possesses their unique epithelial structures and cell types to confer their region-specific functions, which collectively coordinate successful fertilization and pregnancy. MD epithelial fate decisions and differentiation along the craniocaudal axis is dependent on spatiotemporal regulation of intrinsic transcription factors and extrinsic signals derived from the mesenchyme. Findings from genetic mouse models, single-cell sequencing studies, and organoid cultures have significantly advanced our understanding of the cellular and molecular mechanisms of MD regionalization. In this review, we first discuss the diversity of epithelial morphologies and cell types in the female reproductive tract organs. Then, we discuss the roles of key transcription factors (Hox, transcriptional cascade driving multiciliogenesis, Foxa2, and P63), signaling pathways (estrogen/ESR1, Wnt/β-catenin, hedgehog, and retinoic acid), and epigenetic factors (microRNAs, chromatin remodeling factors, and histone modification enzymes) in region-specific MD differentiation. Further deciphering molecular mechanisms of MD craniocaudal patterning will open new avenues to improve our strategies for prevention, diagnosis, and treatment of Müllerian anomalies and female reproductive tract disorders.