Androgen Signaling in Prostatic Sonic Hedgehog Responsive Cells

项目总结 雄激素受体介导的雄激素信号通路对前列腺癌至关重要 胚胎发育、青春期前形态发生、青春期生长和再生。基因突变 睾丸雌性化小鼠的AR基因导致前列腺发育完全缺失。在.期间 胚胎发生，AR最初在前列腺启动之前在泌尿生殖窦间充质中被检测到 发芽和形态发生，其表达在启动后延伸到泌尿生殖窦上皮 前列腺芽和分枝形态发生。早期的组织重组分析已有30多年的历史 AGO证明，间充质而不是上皮性AR信号在诱导 前列腺上皮的发育，为前列腺间质细胞巢的形成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 用于前列腺生后形态发生、生长和再生。重复前列腺再生 雄激素撤换周期进一步证明了雄激素信号转导的重要作用 在前列腺细胞分化和生长中的作用。然而，尽管在过去的30年里做出了重大的研究努力， 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。具体地说，细胞 表达AR的间充质细胞传递雄激素信号调节前列腺的特性 上皮的发育和形态发生仍不清楚。 Sonic Hedgehog信号在前列腺发育、动态平衡和再生中起关键作用 通过间充质-上皮的相互作用。Shh生长因子及其下游效应因子为 在胚胎发生和发育过程中，分别在前列腺上皮细胞和间充质细胞中表达 成人期。最近，利用小鼠遗传工具，我们首次证明了AR的选择性缺失 在间质中，表达Gli1的细胞取消了前列腺胚胎发育和前列腺形成，并且 减少前列腺青春期的生长和再生。此外，我们组织重组的结果 分析表明，间充质AR和Gli1表达的细胞在支持前列腺早期的过程中起着细胞生态位的作用 发育和前列腺体的形成。这些发现为我们提供了对细胞身份的新见解 基质细胞在支持前列腺干/祖细胞功能中的作用，并暗示一种新的 间质雄激素和Shh信号在调节前列腺细胞命运、生长和 更新。基于这些新的和重要的发现，我们提出了一系列实验来测试我们的中心 假设：Shh反应细胞中的间质雄激素信号作为干细胞利基发挥作用 对前列腺早期发育、青春期前形态发生和青春期生长具有重要作用 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.