State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
PLoS Genet. 2018 Aug 13;14(8):e1007463. doi: 10.1371/journal.pgen.1007463. eCollection 2018 Aug.
Meiosis is a germ cell-specific division that is indispensable for the generation of haploid gametes. However, the regulatory mechanisms of meiotic initiation remain elusive. Here, we report that the Wdr62 (WD40-repeat protein 62) is involved in meiotic initiation as a permissive factor rather than an instructive factor. Knock-out of this gene in a mouse model resulted in female meiotic initiation defects. Further studies demonstrated that Wdr62 is required for RA-induced Stra8 expression via the activation of JNK signaling, and the defects in meiotic initiation from Wdr62-deficient female mice could be partially rescued by JNK1 overexpression in germ cells. More importantly, two novel mutations of the WDR62 gene were detected in patients with premature ovarian insufficiency (POI), and these mutations played dominant-negative roles in regulating Stra8 expression. Hence, this study revealed that Wdr62 is involved in female meiotic initiation via activating JNK signaling, which displays a novel mechanism for regulating meiotic initiation, and mutation of WDR62 is one of the potential etiologies of POI in humans.
减数分裂是一种生殖细胞特有的分裂，对于产生单倍体配子是必不可少的。然而，减数分裂起始的调控机制仍然难以捉摸。在这里，我们报告说 Wdr62（WD40 重复蛋白 62）作为一种许可因子而不是指导因子参与减数分裂起始。在小鼠模型中敲除该基因导致雌性减数分裂起始缺陷。进一步的研究表明，Wdr62 通过激活 JNK 信号通路对于 RA 诱导的 Stra8 表达是必需的，并且 Wdr62 缺陷型雌性小鼠减数分裂起始缺陷可以通过在生殖细胞中过表达 JNK1 部分挽救。更重要的是，在患有卵巢早衰 (POI) 的患者中检测到 WDR62 基因的两个新突变，这些突变在调节 Stra8 表达中发挥显性负作用。因此，这项研究揭示了 Wdr62 通过激活 JNK 信号通路参与雌性减数分裂起始，这显示了一种调节减数分裂起始的新机制，并且 WDR62 的突变是人类 POI 的潜在病因之一。
