Sodium-hydrogen exchanger NHA1 and NHA2 control sperm motility and male fertility.
Sodium-hydrogen exchanger NHA1 and NHA2 control sperm motility and male fertility.
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DOI：
10.1038/cddis.2016.65
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发表时间：
2016-03-24
影响因子：
9
通讯作者：
Liu YX
中科院分区：
文献类型：
--
作者：
Chen SR;Chen M;Deng SL;Hao XX;Wang XX;Liu YX
我们之前的工作发现NHA1是一种睾丸特异的钠氢交换器，专门定位于小鼠精子鞭毛的主要部分。我们随后的研究表明，接种NHA1疫苗的雌性小鼠的新生儿数量和受精率显著下降。为了确定NHA1在精子中的生理功能，我们建立了Nha1Fx/Fx，Zp3-Cre(以下简称Nha1 CKO)小鼠，发现Nha1 CKO雄性小鼠存活和生育能力低下，精子活力降低。值得注意的是，在Na1-CKO精子中，可溶性腺苷环化酶(SAC)合成环腺苷酸(CAMP)的作用减弱，cAMP类似物可恢复精子活力。与Nha1 CKO雄性小鼠相似，Nha2Fx/Fx、Zp3-Cre(以下简称Nha2 CKO)雄性小鼠是不育的，这表明这两个Nha基因可能在功能上是多余的。此外，我们证明了缺乏Nha1和Nha2基因的雄性小鼠(以下称为Nha1/2 dKO小鼠)是完全不育的，由于SAC-cAMP信号减弱，精子活力严重下降。重要的是，NHA1在精子中的主片段分布在精子发生中是系统发育保守的。总而言之，我们的数据显示，NHA1和NHA2在离开附睾尾后，作为一个关键的钠氢交换器，负责精子的运动。
Our previous work identified NHA1, a testis-specific sodium–hydrogen exchanger, is specifically localized on the principal piece of mouse sperm flagellum. Our subsequent study suggested that the number of newborns and fertility rate of NHA1-vaccinated female mice are significantly stepped down. In order to define the physiological function of NHA1 in spermatozoa, we generated Nha1Fx/Fx, Zp3-Cre (hereafter called Nha1 cKO) mice and found that Nha1 cKO males were viable and subfertile with reduced sperm motility. Notably, cyclic AMP (cAMP) synthesis by soluble adenylyl cyclase (sAC) was attenuated in Nha1 cKO spermatozoa and cAMP analogs restored sperm motility. Similar to Nha1 cKO males, Nha2Fx/Fx, Zp3-Cre (hereafter called Nha2 cKO) male mice were subfertile, indicating these two Nha genes may be functionally redundant. Furthermore, we demonstrated that male mice lacking Nha1 and Nha2 genes (hereafter called Nha1/2 dKO mice) were completely infertile, with severely diminished sperm motility owing to attenuated sAC-cAMP signaling. Importantly, principal piece distribution of NHA1 in spermatozoa are phylogenetically conserved in spermatogenesis. Collectively, our data revealed that NHA1 and NHA2 function as a key sodium–hydrogen exchanger responsible for sperm motility after leaving the cauda epididymidis.