Department of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, United Kingdom.
PLoS One. 2013 Aug 7;8(8):e71694. doi: 10.1371/journal.pone.0071694. Print 2013.
Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic "ARE-Luc" mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds.
雄激素对于男性和女性的正常发育和生育能力是必需的，它们在生殖道、大脑、心血管系统、平滑肌和骨骼中具有重要作用。雄激素通过雄激素受体 (AR) 发挥作用，AR 是一种配体依赖性转录因子。为了在体内检测和定位 AR 活性，我们生成了表达激活的内源性 AR 控制下的荧光素酶报告基因的转基因“ARE-Luc”小鼠。雄激素介导的荧光素酶活性的体内成像显示，雄性小鼠的一些组织（如预期的那样）以及某些雌性组织具有强烈的表达。在雄性中，睾丸、前列腺、精囊和骨髓均显示出高 AR 活性。在雌性中，卵巢、子宫、网膜组织和乳腺中也有强烈的活性。在两性中，唾液腺、眼睛（及其相关腺体）、脂肪组织、脾脏中也发现了 AR 表达和活性，值得注意的是，大脑的某些区域也存在 AR 表达和活性。荧光素酶蛋白表达与雄激素受体表达位于相同的细胞层。此外，小鼠 AR 表达和活性与人类组织中的 AR 表达非常吻合。抗雄激素比卡鲁胺降低了所有组织中的荧光素酶信号。我们的模型表明，雄激素可以直接通过 AR 在这些组织中发挥作用，而不仅仅是通过雄激素芳香化为雌激素并激活雌激素受体来发挥作用。此外，它直观地展示了 AR 信号在生殖器官正常功能之外的重要性。该模型代表了用于雄激素信号生理和发育分析以及用于表征已知和新型雄激素或抗雄激素化合物的重要工具。
