Crucial roles of mesenchymal Gata2 in murine epididymal development

Androgens drive the morphogenesis and differentiation of the Wolffian duct (WD) into the epididymis, an essential organ for male reproduction, by binding to the androgen receptor (AR). However, it remains unclear whether other transcriptional programs operate beyond the central androgen/AR signaling in promoting WD development. We discovered that mesenchyme-specific deletion of the transcription factor Gata2 resulted in defective epididymal coiling in the corpus and caudal regions. The defective coiling in the absence of mesenchymal Gata2 did not result from androgen signaling deficiency, as there were no abnormalities in testicular morphology, androgen production, or AR/Ar expression, and dihydrotestosterone supplementation did not restore epididymal coiling in cultured WDs. Instead, Gata2 deletion reduced the expression of the mesenchyme- derived factor Inhba and epithelial proliferation, both of which play critical roles in epididymal coiling. The epididymal defect persisted into adulthood, with the uncoiled corpus and caudal epididymis exhibiting abnormal epithelial morphology and lumen environments, resulting in an unfavorable environment for sperm storage. Our results demonstrate the androgen-independent role of mesenchymal GATA2 in promoting epididymal development through Inhba induction and highlight the importance of proper fetal development in male reproduction. Significance StatementTesticular androgens drive the maintenance and differentiation of the Wolffian duct into a coiled and functional epididymis during male sexual differentiation. Our study, however, reveals that the Wolffian duct failed to develop into a coiled and functional epididymis in the absence of mesenchymal Gata2. This defect is not due to androgen signaling deficiency but rather to reduced expression of the mesenchyme-derived factor Inhba and decreased epithelial proliferation. Our results demonstrate the crucial role of GATA2-mediated transcriptional programs beyond the central androgen/androgen receptor signaling in Wolffian duct development.