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首页> 外文期刊>PLoS Genetics >Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration
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Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration

机译：间充质声毒刺猬响应细胞中雄激素信号传导的丧失减少前列腺发育，生长和再生

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Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
机译：通过雄激素信号介导的间充质 - 上皮相互作用来调节前列腺胚胎发育，青春期和成人生长，维护和再生。具体地，在30多年内观察到间充质雄激素信号在前列腺上皮发育中的基本作用。然而，负责这种旁静脉调节和相关机制的间充质细胞的同一性仍然未知。在这里，我们提供了雄激素受体（AR）在Sonic Hedgehog（SHH）响应性Gli1表达细胞中的不可或缺的作用，调节前列腺发育，生长和再生。在胚胎发生期间，在Gli1表达细胞中选择性缺失Ar表达破坏了前列腺芽并损害前列腺萌发和形成。组织重组测定表明，含有Ar缺陷的间充质Gli1表达细胞与野生型泌尿生殖器上皮（UGE）结合源性的泌尿生长学间充质（UGM）未能在雄激素存在下进行正常前列腺组织，揭示了AR在间充质SHH响应细胞中的决定性作用在前列腺发展中。 GLI1表达细胞中AR表达的前燃烧缺失导致雄激素诱导的前列腺生长和再生严重损害。 RNA测序分析显示出与前列腺发育，干细胞和ars缺陷的Gli1表达细胞相关的信号通路的显着改变。在这些改变的途径中，转化生长因子β1（TGFβ1）途径在Ar缺陷的Gli1表达细胞中上调。我们进一步证明了在Ar缺失的前列腺Gli1的细胞中激活TGFβ1信号传导，其抑制通过旁碱调控的前列腺上皮生长。这些数据表明了用于调节前列腺细胞命运，形态发生和更新的GLI1表达细胞Niche中的AR的新作用，并阐明通过SHH反应细胞进行间充和雄激素信号传导的机制引发前列腺上皮的生长和再生。

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