Androgen action in cell fate and communication during prostate development at single-cell resolution

Abstract

Androgens/androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, and regeneration. Specifically, stromal AR-signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were characterized in regulating prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation mesenchymal rather than epithelial cells dysregulates the expression of the master regulators and significantly impairs prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling as cellular niches controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.