Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA 94305-5328, USA.
Differentiation. 2019 May-Jun;107:1-10. doi: 10.1016/j.diff.2019.03.002. Epub 2019 Mar 22.
Androgen signaling is essential for prostate development, morphogenesis, and regeneration. Emerging evidence also indicates a regulatory role of Notch signaling in prostate development, differentiation, and growth. However, the collaborative regulatory mechanisms of androgen and Notch signaling during prostate development, growth, and regeneration are largely unknown. Hairy and Enhancer of Split 1 (Hes1) is a transcriptional regulator of Notch signaling pathways, and its expression is responsive to Notch signaling. Hes1-expressing cells have been shown to possess the regenerative capability to repopulate a variety of adult tissues. In this study, we developed new mouse models to directly assess the role of the androgen receptor in prostatic Hes1-expressing cells. Selective deletion of AR expression in embryonic Hes1-expressing cells impeded early prostate development both in vivo and in tissue xenograft experiments. Prepubescent deletion of AR expression in Hes1-expressing cells resulted in prostate glands containing abnormalities in cell morphology and gland architecture. A population of castration-resistant Hes1-expressing cells was revealed in the adult prostate, with the ability to repopulate prostate epithelium following androgen supplementation. Deletion of AR in Hes1-expressing cells diminishes their regenerative ability. These lines of evidence demonstrate a critical role for the AR in Notch-responsive cells during the course of prostate development, morphogenesis, and regeneration, and implicate a mechanism underlying interaction between the androgen and Notch signaling pathways in the mouse prostate.
雄激素信号对于前列腺的发育、形态发生和再生是必不可少的。新出现的证据也表明 Notch 信号在前列腺的发育、分化和生长中具有调节作用。然而，雄激素和 Notch 信号在前列腺发育、生长和再生过程中的协同调控机制在很大程度上尚不清楚。Hairy 和 Enhancer of Split 1（Hes1）是 Notch 信号通路的转录调节因子，其表达对 Notch 信号有反应。已经表明 Hes1 表达细胞具有再生能力，可以重新填充各种成年组织。在这项研究中，我们开发了新的小鼠模型，以直接评估雄激素受体在前列腺 Hes1 表达细胞中的作用。在体内和组织异种移植实验中，胚胎期 Hes1 表达细胞中 AR 表达的选择性缺失会阻碍早期前列腺的发育。青春期前 Hes1 表达细胞中 AR 表达的缺失会导致前列腺腺体内细胞形态和腺管结构异常。在成年前列腺中发现了一群抗阉割的 Hes1 表达细胞，它们在雄激素补充后能够重新填充前列腺上皮。在 Hes1 表达细胞中删除 AR 会降低其再生能力。这些证据表明，AR 在前列腺发育、形态发生和再生过程中 Notch 反应细胞中起着关键作用，并暗示了雄激素和 Notch 信号通路在小鼠前列腺中相互作用的一种机制。
