Loss of the Na+/H+ exchanger NHE8 causes male infertility in mice by disrupting acrosome formation
Loss of the Na+/H+ exchanger NHE8 causes male infertility in mice by disrupting acrosome formation
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DOI：
10.1074/jbc.m117.784108
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发表时间：
2017-06-30
影响因子：
4.8
通讯作者：
Jentsch, Thomas J.
中科院分区：
文献类型：
--
作者：
Oberheide, Karina;Puchkov, Dmytro;Jentsch, Thomas J.
哺乳动物精子的特征是在精子核的前部有一个特殊的分泌细胞器，即顶体，它对雄性生育力至关重要。它是由高尔基体衍生的囊泡融合而成。我们在这里表明，主要高尔基居民Na+/H+交换NHE 8定位于精子细胞的顶体发育。与野生型小鼠相似，Nhe 8（-/-）小鼠产生高尔基体衍生的囊泡，顶体标记阳性，并附着在细胞核上，但这些囊泡未能形成大的顶体颗粒和顶体帽。Nhe 8（-/-）小鼠的精子完全缺乏顶体，圆头，线粒体分布异常，活力降低，导致选择性雄性不育。值得注意的是，在人类男性不育的原因之一--球形精子症中也发现了类似的特征。生殖细胞特异性的，但不是支持细胞特异性的NHE 8破坏概括了球形精子症的表型，表明NHE 8在精子发生中的作用是生殖细胞内在的。我们的工作揭示了NHE 8在顶体生物发生中的关键作用，并表明某些形式的人类球形精子症可能是由这种Na+/H+交换器功能丧失引起的。它指出NHE 8是人类球形精子症的候选基因，也是男性避孕的可能药物靶点。
Mammalian sperm feature a specialized secretory organelle on the anterior part of the sperm nucleus, the acrosome, which is essential for male fertility. It is formed by a fusion of Golgi-derived vesicles. We show here that the predominantly Golgi-resident Na+/H+ exchanger NHE8 localizes to the developing acrosome of spermatids. Similar to wild-type mice, Nhe8(-/-) mice generated Golgi-derived vesicles positive for acrosomal markers and attached to nuclei, but these vesicles failed to form large acrosomal granules and the acrosomal cap. Spermatozoa from Nhe8(-/-) mice completely lacked acrosomes, were round-headed, exhibited abnormal mitochondrial distribution, and displayed decreased motility, resulting in selective male infertility. Of note, similar features are also found in globozoospermia, one of the causes of male infertility in humans. Germ cell-specific, but not Sertoli cell-specific Nhe8 disruption recapitulated the globozoospermia phenotype, demonstrating that NHE8's role in spermiogenesis is germ cell-intrinsic. Our work has uncovered a crucial role of NHE8 in acrosome biogenesis and suggests that some forms of human globozoospermia might be caused by a loss of function of this Na+/H+ exchanger. It points to NHE8 as a candidate gene for human globozoospermia and a possible drug target for male contraception.