Estrogen-dependent and -independent estrogen receptor-alpha signaling separately regulate male fertility.
Estrogen-dependent and -independent estrogen receptor-alpha signaling separately regulate male fertility.
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DOI：
10.1210/en.2008-1016
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发表时间：
2009-06
期刊：
影响因子：
4.8
通讯作者：
K. Sinkevicius;M. Lainé;T. Lotan;K. Woloszyn;J. Richburg;G. Greene
中科院分区：
文献类型：
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作者：
K. Sinkevicius;M. Lainé;T. Lotan;K. Woloszyn;J. Richburg;G. Greene
雌激素受体- α (er - α)在男性生殖道发育和生育中起着重要作用。为了确定雌激素依赖性和非依赖性erα机制是否参与雄性生育，我们研究了雄性雌激素无反应erα敲入小鼠。这些动物在erα的配体结合区域有一个点突变（G525L），显著降低了与内源性雌激素的相互作用和应答，但不影响与配体无关的erα途径的生长因子激活。令人惊讶的是，我们发现与配体无关的er - α信号通过调节输出小管液的再吸收，对集中附睾精子至关重要。相反，雌激素依赖性erα信号是生殖细胞生存所必需的，最有可能通过支持支持细胞功能。通过使用erα选择性合成激动剂丙基吡唑三醇治疗雌激素无应答性erα敲入（ENERKI）小鼠，我们发现雄性生育能力需要新生儿雌激素介导的erα信号传导。因此，我们的工作表明，雌激素依赖性和非依赖性途径在雄性小鼠生殖道发育中都起着可分离的作用，erα在人类不育中的作用应该更仔细地研究。
Estrogen receptor-alpha (ERalpha) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERalpha mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERalpha knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERalpha that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERalpha pathways. Surprisingly, we found that ligand-independent ERalpha signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERalpha signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERalpha knock-in (ENERKI) mice with the ERalpha selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERalpha in vivo, we discovered male fertility required neonatal estrogen-mediated ERalpha signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERalpha in human infertility should be examined more closely.