Ma Yanbin, Liu Yuxin, Xu Man, Yin Xinhuan, Hu Chenyu, Yang Xiaohang, Ge Wanzhong
Division of Human Reproduction and Developmental Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.
J Mol Med (Berl). 2025 Feb;103(2):239-253. doi: 10.1007/s00109-025-02516-1. Epub 2025 Jan 24.
Primary ovarian insufficiency (POI) is a disease defined as a reduction in ovarian function under the age of 40 and represents the main cause of female infertility. In recent years, many genetic mutations associated with POI have been identified using high-throughput sequencing technology. However, one big challenge today is to determine the disease-causing gene associations through functional assessment. Here, we develop a Drosophila model to study the POI-associated genes and provide in vivo functional evidence to validate the POI-causing genes. We use two different Gal4 drivers, in combination with RNAi transgene, and systematically knockdown 51 genes associated with POI. We show that 22 and 17 genes are required for female fertility and ovarian development in somatic and germline cells, respectively. Moreover, we also focus on AlaRS-m, the Drosophila ortholog of the human AARS2 gene, for further functional characterization. Depletion of AlaRS-m in ovarian somatic cells leads to decreased female fertility and a reduction in ovary size, as well as egg chamber degeneration. We also provide evidence that AlaRS-m deficiency causes mitochondrial dysfunction, overproduction of ROS, and apoptotic cell death. Our findings demonstrate that Drosophila can be used as a platform to assess the functional significance of POI-associated genes identified in genomic studies and illustrate the molecular mechanism underlying the pathogenesis of POI. KEY MESSAGES: • One hundred fourteen genes associated with POI are identified, and 76 of them have Drosophila orthologs. • Twenty-two genes and 17 genes are required for female fertility when knocked down in the Drosophila ovarian somatic cells and germline cells, respectively. • AlaRS-m/AARS2 deficiency causes female fertility defects with egg chamber degeneration.
原发性卵巢功能不全（POI）是一种定义为40岁以下卵巢功能减退的疾病，是女性不孕的主要原因。近年来，利用高通量测序技术已经鉴定出许多与POI相关的基因突变。然而，当今一个巨大的挑战是通过功能评估来确定致病基因关联。在此，我们构建了一个果蝇模型来研究与POI相关的基因，并提供体内功能证据来验证导致POI的基因。我们使用两种不同的Gal4驱动子，结合RNAi转基因，系统地敲低51个与POI相关的基因。我们发现，分别有22个和17个基因对于体细胞和生殖细胞中的雌性生育力和卵巢发育是必需的。此外，我们还聚焦于人类AARS2基因在果蝇中的直系同源基因AlaRS-m，进行进一步的功能表征。在卵巢体细胞中敲低AlaRS-m会导致雌性生育力下降、卵巢大小减小以及卵室退化。我们还提供证据表明，AlaRS-m缺陷会导致线粒体功能障碍、活性氧过度产生以及细胞凋亡。我们的研究结果表明，果蝇可用作一个平台，来评估基因组研究中鉴定出的与POI相关基因的功能意义，并阐明POI发病机制的分子基础。关键信息：• 鉴定出114个与POI相关的基因，其中76个有果蝇直系同源基因。• 在果蝇卵巢体细胞和生殖细胞中分别敲低时，22个基因和17个基因对于雌性生育力是必需的。• AlaRS-m/AARS2缺陷导致雌性生育力缺陷并伴有卵室退化。
