NHC Key Laboratory of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, School of Pharmacy, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Biol Reprod. 2023 Oct 13;109(4):450-460. doi: 10.1093/biolre/ioad076.
Multiple morphological abnormalities of the flagella, a severe form of asthenozoospermia, can lead to male infertility. Recent studies have implicated an association between human CFAP70 deficiency and multiple morphological abnormalities of the flagella; however, the underlying biological mechanism and supporting experimental evidence in animal models remain unclear. To address this gap, we used CRISPR/Cas9 technology to generate Cfap70-deficient mice to investigate the relationship between Cfap70 deficiency and multiple morphological abnormalities of the flagella. Our findings show that the loss of CFAP70 leads to multiple morphological abnormalities of the flagella and spermiogenesis defects. Specifically, the lack of CFAP70 impairs sperm flagellum biogenesis and head shaping during spermiogenesis. Late-step spermatids from Cfap70-deficient mouse testis exhibited club-shaped sperm heads and abnormal disassembly of the manchette. Furthermore, we found that CFAP70 interacts with DNAI1 and DNAI2; Cfap70 deficiency also reduces the level of AKAP3 in sperm flagella, indicating that CFAP70 may participate in the flagellum assembly and transport of flagellar components. These findings provide compelling evidence implicating Cfap70 as a causative gene of multiple morphological abnormalities of the flagella and highlight the consequences of CFAP70 loss on flagellum biogenesis.
鞭毛的多种形态异常，即严重的弱精症，可导致男性不育。最近的研究表明，人类 CFAP70 缺乏与鞭毛的多种形态异常有关；然而，其潜在的生物学机制和动物模型的支持性实验证据尚不清楚。为了解决这一差距，我们使用 CRISPR/Cas9 技术生成 Cfap70 缺陷型小鼠，以研究 Cfap70 缺乏与鞭毛的多种形态异常之间的关系。我们的研究结果表明，CFAP70 的缺失会导致鞭毛的多种形态异常和精子发生缺陷。具体而言，CFAP70 的缺乏会损害精子鞭毛的生物发生和精子发生过程中的头部形成。来自 Cfap70 缺陷型小鼠睾丸的晚期精子细胞表现出棒状精子头部和顶体囊的异常解体。此外，我们发现 CFAP70 与 DNAI1 和 DNAI2 相互作用；Cfap70 缺乏还会降低精子鞭毛中 AKAP3 的水平，表明 CFAP70 可能参与鞭毛的组装和鞭毛成分的运输。这些发现为 Cfap70 作为鞭毛多种形态异常的致病基因提供了有力证据，并强调了 CFAP70 缺失对鞭毛生物发生的影响。
