Cfap61, Cilia- and flagella-associated protein 61, is a conserved component of the calmodulin-and radial spoke-associated complex (CSC) of cilia. It plays a crucial role in sperm flagellum formation, and thus is essential for male fertility. Its function is likely related to the axoneme stabilization in sperm cells, an important process during spermatogenesis [1,3,4,5,6].

Cfap61 knockout mouse models have recapitulated the infertility phenotype observed in human CFAP61 mutations [1]. In Cfap61 -/- spermatid development, the assembly of radial spoke components is impaired in the early stages. As spermiogenesis progresses, the axoneme becomes unstable and scatters, and the distribution of intraflagellar transport proteins is disrupted [1]. Also, Cfap61 knockdown in Leydig cells reduces cell viability and testosterone secretion, and enhances apoptosis via the MAPK/COX-2 pathway, further aggravating male infertility [2].

In conclusion, Cfap61 is essential for spermatogenesis, with its function in sperm flagellum formation and maintenance of axoneme stability being critical. The Cfap61 knockout mouse models have been instrumental in revealing its role in male infertility, providing insights into the underlying mechanisms and potential therapeutic targets for male infertility [1,2,3,4,5,6].

References:

1. Liu, Siyu, Zhang, Jintao, Kherraf, Zine Eddine, Ray, Pierre F, Liu, Mingxi. 2021. CFAP61 is required for sperm flagellum formation and male fertility in human and mouse. In Development (Cambridge, England), 148, . doi:10.1242/dev.199805. https://pubmed.ncbi.nlm.nih.gov/34792097/

2. Zhu, Wenkai, Mao, Jing, Qin, Jianxin, Chen, Xia. 2023. CFAP61 knockdown aggravates male infertility by inhibiting testosterone secretion by Leydig cells via the MAPK/COX-2 pathway. In Functional & integrative genomics, 23, 340. doi:10.1007/s10142-023-01271-1. https://pubmed.ncbi.nlm.nih.gov/37982895/

3. Hu, Tongyao, Meng, Lanlan, Tan, Chen, Lin, Ge, Tan, Yue-Qiu. 2022. Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia. In Journal of medical genetics, 60, 144-153. doi:10.1136/jmedgenet-2021-108249. https://pubmed.ncbi.nlm.nih.gov/35387802/

4. Ma, Ao, Zeb, Aurang, Ali, Imtiaz, Ma, Hui, Shi, Qinghua. 2022. Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility. In Frontiers in cell and developmental biology, 9, 803818. doi:10.3389/fcell.2021.803818. https://pubmed.ncbi.nlm.nih.gov/35174165/

5. Barbotin, Anne-Laure, Boursier, Angèle, Jourdain, Anne-Sophie, Ghoumid, Jamal, Smol, Thomas. 2024. Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella. In Journal of assisted reproduction and genetics, 41, 1499-1505. doi:10.1007/s10815-024-03139-0. https://pubmed.ncbi.nlm.nih.gov/38775994/

6. Huang, Tao, Yin, Yingying, Liu, Chao, Liu, Hongbin, Ma, Jinlong. 2020. Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella. In Science bulletin, 65, 854-864. doi:10.1016/j.scib.2020.01.023. https://pubmed.ncbi.nlm.nih.gov/36659204/