Contribution of the Wolffian duct mesenchyme to the formation of the female reproductive tract

Abstract The female reproductive tract develops from its embryonic precursor, the Müllerian duct. In close proximity to the Müllerian duct lies the precursor for the male reproductive tract, the Wolffian duct, which is eliminated in the female embryo during sexual differentiation. We discovered that a component of the Wolffian duct, its mesenchyme, is not eliminated after sexual differentiation. Instead, the Wolffian duct mesenchyme underwent changes in transcriptome and chromatin accessibility from male tract to female tract identity, and became a unique mesenchymal population in the female reproductive tract with localization and transcriptome distinct from the mesenchyme derived from the Müllerian duct. Partial ablation of the Wolffian duct mesenchyme stunted the growth of the fetal female reproductive tract. These findings reveal a new fetal origin of mesenchymal tissues for female reproductive tract formation and reshape our understanding of sexual differentiation of reproductive tracts. Significance statementA female embryo initially possesses both the primitive female and male reproductive tracts, also known as the Müllerian and Wolffian duct. During sexual differentiation, the female eliminates the Wolffian duct and maintains the Müllerian duct that eventually differentiates into the female reproductive tract organs. However, in this paper, we show the female embryo retains mesenchymal cells surrounding the Wolffian duct for its reproductive tract formation. When incorporated into the female reproductive tract organs, the Wolffian duct mesenchyme shows unique anatomical localization and transcriptome and plays critical roles in female reproductive tract growth. This discovery provides new insights into female reproductive tract development and advances our understanding of sexual differentiation of reproductive tracts.