Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells

PROJECT SUMMARY The androgen-signaling pathway mediated through the androgen receptor is essential for prostate embryonic development, prepubescent morphogenesis, and pubertal growth and regeneration. Mutation of the Ar gene in testicular feminized mice results in the complete absence of prostate development. During embryogenesis, the AR is initially detected in the urogenital sinus mesenchyme prior to the initiation of prostate budding and morphogenesis, and its expression extends to the urogenital sinus epithelium after the initiation of prostatic budding and branching morphogenesis. Early tissue recombination assays done more than 30 years ago demonstrated that mesenchymal, rather than epithelial AR signaling plays a decisive role in inducing development of the prostatic epithelium, providing the first scientific evidence for a stromal cell niche in supporting prostate stem cell initiated prostate early development. Androgen signaling still remains essential for prostatic postnatal morphogenesis, growth and regeneration. Prostatic regeneration through repeated cycles of androgen withdrawal and replacement further demonstrates the essential role of androgen signaling in prostate cell differentiation and growth. However, despite significant research effort in the past 30 years, the underlying mechanisms by which androgens facilitate prostatic stem/progenitor cells through paracrine interactions between prostatic epithelium and mesenchyme are largely unknown. Specifically, the cellular properties of the AR-expressing mesenchymal cells that can convey androgen signaling to regulate prostatic epithelial development and morphogenesis still remain unclear. Sonic hedgehog signaling plays a critical role in prostate development, homeostasis, and regeneration through mesenchymal–epithelial interactions. The Shh growth factors and its downstream effectors are expressed in either prostatic epithelial or mesenchymal cells, respectively, during embryogenesis and adulthood. Recently, using mouse genetic tools, we demonstrate for the first time that selective deletion of AR in mesenchymal Gli1-expressing cells abolishes prostatic embryonic development and prostate formation, and diminishes prostate pubertal growth and regeneration. In addition, results from our tissue recombination assays showed that mesenchymal AR and Gli1 expressing cells act as cell niches in supporting prostate early development and prostatic gland formation. These findings provide fresh insight into the cellular identity of the stromal cell niche in supporting prostate stem/progenitor function in the prostate, and implicate a new regulatory mechanism for stromal androgen and Shh signaling in regulating prostatic cell fate, growth, and renewal. Based on these new and significant findings, we propose a series of experiments to test our central hypothesis: stromal androgen signaling in Shh-responsive cells acts as a stem cell niche and plays an essential role for prostate early development, prepubescent morphogenesis, and pubertal growth and regeneration.