Department of Cellular and Molecular Medicine, Molecular Endocrinology Laboratory, KU Leuven, Leuven, 3000, Belgium.
Department of Chronic Diseases and Metabolism, Clinical and Experimental Endocrinology, KU Leuven, Leuven, 3000, Belgium.
Endocrinology. 2022 Sep 1;163(9). doi: 10.1210/endocr/bqac104.
The androgen receptor (AR) plays a central role in the development and maintenance of the male phenotype. The binding of androgens to the receptor induces interactions between the carboxyterminal ligand-binding domain and the highly conserved 23FQNLF27 motif in the aminoterminal domain. The role of these so-called N/C interactions in AR functioning is debated. In vitro assays show that mutating the AR in the 23FQNLF27 motif (called ARNoC) attenuates the AR transactivation of reporter genes, has no effect on ligand binding, but does affect protein-protein interactions with several AR coregulators. To test the in vivo relevance of the N/C interaction, we analyzed the consequences of the genomic introduction of the ARNoC mutation in mice. Surprisingly, the ARNoC/Y mice show a normal male development, with unaffected male anogenital distance and normal accessory sex glands, male circulating androgen levels, body composition, and fertility. The responsiveness of androgen target genes in kidney, prostate, and testes was also unaffected. We thus conclude that the N/C interactions in the AR are not essential for the development of a male phenotype under normal physiological conditions.
雄激素受体（AR）在男性表型的发育和维持中起着核心作用。雄激素与受体结合诱导羧基末端配体结合域与氨基末端高度保守的 23FQNLF27 基序之间的相互作用。这些所谓的 N/C 相互作用在 AR 功能中的作用存在争议。体外实验表明，突变 AR 中的 23FQNLF27 基序（称为 ARNoC）会减弱 AR 对报告基因的转录激活作用，对配体结合没有影响，但确实会影响与几个 AR 核心调节剂的蛋白-蛋白相互作用。为了测试 N/C 相互作用的体内相关性，我们分析了 ARNoC 突变在小鼠中的基因组引入的后果。令人惊讶的是，ARNoC/Y 小鼠表现出正常的男性发育，男性肛殖距离和正常附属性腺体、男性循环雄激素水平、身体成分和生育能力不受影响。肾脏、前列腺和睾丸中的雄激素靶基因的反应性也不受影响。因此，我们得出结论，在正常生理条件下，AR 中的 N/C 相互作用对于男性表型的发育不是必需的。
