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发育，形态发生和再生至关重要。新兴证据还表明，Notch信号在前列腺发育，分化和生长中起调节作用。然而，在前列腺发育，生长和再生期间雄激素和Notch信号传导的协同调节机制在很大程度上是未知的。毛发和分裂1增强子（Hes1）是Notch信号通路的转录调节因子，其表达对Notch信号有响应。已表明表达Hes1的细胞具有再生能力，可重新繁殖各种成人组织。在这项研究中，我们开发了新的小鼠模型来直接评估雄激素受体在表达Hes1的前列腺细胞中的作用。体内和组织异种移植实验。青春期前表达Hes1的细胞中AR表达的缺失导致前列腺含有细胞形态和腺结构异常。在成年前列腺中发现了一群去势抵抗性的Hes1表达细胞，并在补充雄激素后具有重新填充前列腺上皮的能力。表达Hes1的细胞中AR的缺失会降低其再生能力。这些证据表明，AR在前列腺发育，形态发生和再生过程中在Notch反应性细胞中起关键作用，并暗示了小鼠前列腺中雄激素和Notch信号通路之间相互作用的潜在机制。