Ndrg3 gene regulates DSB repair during meiosis through modulation the ERK signal pathway in the male germ cells

Hongjie Pan,Xiaohua Jiang,Yuan Bi,Runsheng Li,Qi Qi,Hanwei Jiang,Qinghua Shi,Jian Wang,Xuan Zhang,Liu Wang

doi:10.1038/srep44440

Abstract

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.

Highlights

Ndrg[3] belongs to the N-myc down-regulated gene (NDRG) family[23,24]
The results showed that NDRG3 protein was detected in germ cells including spermatogonia, spermatocytes and spermatids at 12–36 dpp (Fig. 1c), indicating that the Ndrg[3] gene functioned in the male germ cell development during the spermatogenesis
We further compared the mRNA and protein levels of NDRG3 in spermatogonia, meiosis I prophase subgroups, spermatids and sertoli cells. Both of the results showed the expression of NDRG3 was exclusively in germ cells and largely induced in the meiosis I prophase spermatocytes and spermatids compared with the spermatogonium group. (Fig. 1d and e), implying that NDRG3 exerted the physiological role shortly after the initiation of the meiosis

Summary

Introduction

Ndrg[3] belongs to the N-myc down-regulated gene (NDRG) family[23,24]. The 5α-dihydrotestosterone regulated Ndrg[3] at the beginning of spermatogenesis further implied the function of Ndrg[3] gene may possibly be involved in spermatogenesis[31]. We detected the temporo-spatial expression pattern of Ndrg[3]. It was tightly associated with meiosis progression in testis. Our genetically modified mouse model showed the haplo-insufficiency of Ndrg[3] gene impaired the meiosis in the male germ cells, indicating the biological role of Ndrg[3] in spermatogenesis. This study will be helpful for providing a new prospect that how metabolite lactate influences meiosis in the male germ cells

Methods

Results

Conclusion