College of Animal Science and Technology, Nanjing Agricultural University, 210095, Nanjing, China.
Center for Reproductive Medicine, Peking University Third Hospital, 100191, Beijing, China.
Cell Death Dis. 2019 Jun 17;10(7):474. doi: 10.1038/s41419-019-1720-0.
Reproductive problem has been one of the top issues for women health worldwide in recent decades. As a typical female disease, primary ovarian insufficiency (POI) results in a loss of ovarian follicles and oocytes that thus destroys women fertility. However, due to the complex of POI etiology and rare resource of human POI oocytes, few biomarkers have been identified in clinics and no effective strategy could be applied to treat POI patients. In the search of possible association between DNA damage and POI by Smart-Seq2 and RT profiler PCR array, we find that BRCA2, a core DNA repair gene for homologous recombination shows significantly lower expression in two POI patient oocytes. In line with this, we generated oocyte-specific knockout mouse model driven by Gdf9-Cre. The Brca2-deficient mice are infertile because of the arrested follicle development and defective oocyte quality caused by the accumulation of DNA damage. Notably, ectopic expression of Brca2 in Brca2-deficient oocytes could partially restore the oocyte maturation and chromosome stability. Collectively, our data assign a definite deficiency to BRCA2 as a POI driver during follicle development and oocyte maturation, and provide a potential fertility treatment strategy for POI patients induced by BRCA2 deficiency.
生殖问题是近几十年来全球女性健康的首要问题之一。作为一种典型的女性疾病，原发性卵巢功能不全（POI）导致卵巢卵泡和卵母细胞的丧失，从而破坏了女性的生育能力。然而，由于 POI 病因的复杂性和人类 POI 卵母细胞的稀有资源，临床上尚未鉴定出许多生物标志物，也没有有效的策略可用于治疗 POI 患者。在通过 Smart-Seq2 和 RT profiler PCR 阵列寻找 DNA 损伤与 POI 之间的可能关联时，我们发现 BRCA2，一种同源重组的核心 DNA 修复基因，在两个 POI 患者卵母细胞中的表达明显较低。与此一致，我们通过 Gdf9-Cre 驱动产生了卵母细胞特异性敲除小鼠模型。由于 DNA 损伤的积累导致卵泡发育停滞和卵母细胞质量缺陷，Brca2 缺陷小鼠不育。值得注意的是，Brca2 在 Brca2 缺陷卵母细胞中的异位表达可以部分恢复卵母细胞成熟和染色体稳定性。总之，我们的数据明确将 BRCA2 确定为卵泡发育和卵母细胞成熟过程中的 POI 驱动因素，并为 BRCA2 缺陷引起的 POI 患者提供了一种潜在的生育治疗策略。
