Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells

项目摘要 通过雄激素受体介导的雄激素信号通路对于前列腺增生是必需的。 胚胎发育、青春期前形态发生和青春期生长和再生。突变 睾丸雌性化小鼠中的Ar基因导致完全没有前列腺发育。期间 在胚胎发育中，AR最初在前列腺发育开始之前在尿生殖窦间充质中检测到。 出芽和形态发生，其表达延伸到尿生殖窦上皮后，启动 前列腺出芽和分支形态发生。早期的组织重组检测已经进行了30多年 以前的研究表明，间充质而不是上皮AR信号在诱导细胞凋亡中起决定性作用。 前列腺上皮细胞的发育，为前列腺增生中的基质细胞小生境提供了第一个科学证据。 支持前列腺干细胞启动前列腺早期发育。雄激素信号仍然是必不可少的 前列腺产后形态发生、生长和再生。前列腺再生通过反复 雄激素戒断和替代的周期进一步证明了雄激素信号传导的重要作用， 在前列腺细胞分化和生长中的作用。然而，尽管在过去的30年里进行了大量的研究， 雄激素通过旁分泌促进前列腺干/祖细胞的潜在机制 前列腺上皮和间质之间的相互作用在很大程度上是未知的。具体来说， 表达AR的间充质细胞的性质，可以传递雄激素信号以调节前列腺 上皮发育和形态发生仍然不清楚。 Sonic hedgehog信号在前列腺发育、稳态和再生中起着关键作用 通过间质-上皮相互作用。Shh生长因子及其下游效应物是 在胚胎发生过程中分别在前列腺上皮细胞或间充质细胞中表达， 成年最近，使用小鼠遗传工具，我们首次证明了选择性缺失AR， 在表达间充质Gli 1的细胞中，前列腺胚胎发育和前列腺形成被破坏， 减少前列腺青春期的生长和再生。另外，我们的组织重组 分析表明，间充质AR和Gli 1表达细胞作为细胞龛在支持前列腺早期 发育和前列腺形成。这些发现提供了新的见解细胞身份的 基质细胞小生境在支持前列腺干/祖细胞功能的前列腺，并暗示了一个新的 间质雄激素和Shh信号在调节前列腺细胞命运、生长和增殖中的调节机制， 退款基于这些新的和重要的发现，我们提出了一系列的实验来测试我们的中央 假设：Shh反应细胞中的间质雄激素信号传导作为干细胞小生境， 前列腺早期发育、青春期前形态发生和青春期生长的重要作用， 再生

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.