Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA.
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Cell Rep. 2021 Aug 17;36(7):109557. doi: 10.1016/j.celrep.2021.109557.
Molecular mechanisms by which androgens signal through the androgen receptor (AR) to maintain male fertility are poorly understood. Transgenic mice were produced expressing mutant ARs that can only (1) alter gene transcription through the classical response pathway (AR-C) or (2) activate kinase signaling cascades via the nonclassical pathway (AR-NC). AR-C is sufficient to produce sperm and fertility. Haploid germ cell production, the blood-testis barrier, and spermatid migration are supported by AR-NC. Gene expression essential for chromosome synapsis during meiosis requires AR-C. We identify targets of androgen signaling required for male fertility and provide a mechanistic explanation for meiotic germ cell arrest in the absence of androgen signaling. Prostate differentiation occurs with AR-C alone, but full development requires synergistic nonclassical signaling. Both AR signaling pathways are necessary for normal male reproductive tract development and function, validating our mouse models for studies of AR functions in other target tissues.
雄激素通过雄激素受体 (AR) 发挥作用以维持男性生育力的分子机制尚未完全明了。现已制备出表达突变型 AR 的转基因小鼠，这些突变型 AR 只能（1）通过经典反应途径（AR-C）改变基因转录，或（2）通过非经典途径（AR-NC）激活激酶信号级联反应。AR-C 足以产生精子和生育能力。AR-NC 支持单倍体生殖细胞的产生、血睾屏障和精母细胞迁移。减数分裂过程中染色体联会所必需的基因表达需要 AR-C。我们确定了雄激素信号所必需的靶标，以阐明在缺乏雄激素信号的情况下减数分裂生殖细胞停滞的机制。前列腺分化仅发生在 AR-C 存在的情况下，但完全发育需要协同的非经典信号。AR 信号通路对于正常的男性生殖道发育和功能都是必需的，这验证了我们的小鼠模型可用于研究 AR 在其他靶组织中的功能。
