Ndrg3 gene regulates DSB repair during meiosis through modulation the ERK signal pathway in the male germ cells.
Ndrg3 gene regulates DSB repair during meiosis through modulation the ERK signal pathway in the male germ cells.
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Ndrg3 基因通过调节雄性生殖细胞中的 ERK 信号通路来调节减数分裂期间的 DSB 修复
DOI：
10.1038/srep44440
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发表时间：
2017-03-14
影响因子：
4.6
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Pan H;Zhang X;Jiang H;Jiang X;Wang L;Qi Q;Bi Y;Wang J;Shi Q;Li R
N-myc下游调节基因(NDRG)家族由4个成员组成，即NDRG-1、-2、-3、-4。在生理学上，我们发现Ndrg3是一个在小鼠胚胎发育早期导致同源致死性的关键基因，它调控着小鼠的雄性减数分裂。Ndrg3在生殖细胞中表达增强，在粗线期精母细胞中达到高峰。Ndrg3基因单缺失导致男性早熟亚不育症。在Ndrg3+/−生殖细胞中，DSB修复和联会复合体形成等减数分裂事件受到损害。观察到减数分裂前期进程和精子发生的障碍。在机制上，杂合子睾丸中检测到pERK1/2信号的减弱。在我们的初级精母细胞培养系统中，我们发现乳酸在体外通过ERK1/2信号通路促进雄性小鼠生殖细胞的DSB修复。Ndrg3基因的缺失减弱了ERK的激活，进而导致小鼠雄性生殖细胞DSB修复的异常。综上所述，我们报道了Ndrg3基因调节乳酸诱导的ERK通路以促进雄性生殖细胞的DSB修复，从而进一步调节雄性小鼠的减数分裂和随后的生育。
The N-myc downstream regulated gene (NDRG) family consists of 4 members, NDRG-1, -2, -3, -4. Physiologically, we found Ndrg3, a critical gene which led to homologous lethality in the early embryo development, regulated the male meiosis in mouse. The expression of Ndrg3 was enhanced specifically in germ cells, and reached its peak level in the pachytene stage spermatocyte. Haplo-insufficiency of Ndrg3 gene led to sub-infertility during the male early maturation. In the Ndrg3+/− germ cells, some meiosis events such as DSB repair and synaptonemal complex formation were impaired. Disturbances on meiotic prophase progression and spermatogenesis were observed. In mechanism, the attenuation of pERK1/2 signaling was detected in the heterozygous testis. With our primary spermatocyte culture system, we found that lactate promoted DSB repair via ERK1/2 signaling in the male mouse germ cells in vitro. Deficiency of Ndrg3 gene attenuated the activation of ERK which further led to the aberrancy of DSB repair in the male germ cells in mouse. Taken together, we reported that Ndrg3 gene modulated the lactate induced ERK pathway to facilitate DSB repair in male germ cells, which further regulated meiosis and subsequently fertility in male mouse.