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 found that mesenchyme-specific deletion of the transcription factor Gata2 resulted in defective epididymal coiling in the corpus and caudal regions. The defective coiling did not result from androgen signaling deficiency, as there were no abnormalities in testicular androgen production, AR/Ar expression, or androgen-responsive genes, and dihydrotestosterone supplementation did not restore epididymal coiling in cultured WDs. Instead, Gata2 deletion led to the loss of epididymal identity, as evidenced by the reduced expression of epididymal mesenchymal markers. 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 and highlight the importance of proper fetal development in male reproduction.