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CCDC146 is required for sperm flagellum biogenesis and male fertility in mice

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Abstract

Multiple morphological abnormalities of the flagella (MMAF) is a severe disease of male infertility, while the pathogenetic mechanisms of MMAF are still incompletely understood. Previously, we found that the deficiency of Ccdc38 might be associated with MMAF. To understand the underlying mechanism of this disease, we identified the potential partner of this protein and found that the coiled-coil domain containing 146 (CCDC146) can interact with CCDC38. It is predominantly expressed in the testes, and the knockout of this gene resulted in complete infertility in male mice but not in females. The knockout of Ccdc146 impaired spermiogenesis, mainly due to flagellum and manchette organization defects, finally led to MMAF-like phenotype. Furthermore, we demonstrated that CCDC146 could interact with both CCDC38 and CCDC42. It also interacts with intraflagellar transport (IFT) complexes IFT88 and IFT20. The knockout of this gene led to the decrease of ODF2, IFT88, and IFT20 protein levels, but did not affect CCDC38, CCDC42, or ODF1 expression. Additionally, we predicted and validated the detailed interactions between CCDC146 and CCDC38 or CCDC42, and built the interaction models at the atomic level. Our results suggest that the testis predominantly expressed gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility, and its mutations might be associated with MMAF in some patients.

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All the data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Jingnan Liang and Pengyan Xia for their help with transmission electron microscopy, Chunli Li for his help with scanning electron microscopy, and Guofeng Zhou for his help with the protein-protein docking experiment. This work was supported by the National Science Fund for Distinguished Young Scholars (81925015) and the National Natural Science Foundation of China (Grant No. 91649202).

Funding

This work was supported by the National Science Fund for Distinguished Young Scholars (Grant No. 81925015) and the National Natural Science Foundation of China (Grant No. 91649202).

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Author notes

  1. Yanjie Ma and Bingbing Wu have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Stem Cell and Regenerative Medicine Innovation Institute, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, 100101, China

    Yanjie Ma, Bingbing Wu, Yinghong Chen, Shuang Ma, Chao Liu, Jianguo Zhao & Wei Li

  2. Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, No. 9 Jinsui Road, Tianhe District, Guangzhou, 510623, China

    Yanjie Ma, Bingbing Wu, Yinghong Chen, Shuang Ma, Liying Wang, Tingting Han, Xiaolei Lin, Fulin Yang, Chao Liu & Wei Li

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yanjie Ma, Bingbing Wu, Yinghong Chen, Shuang Ma, Chao Liu, Jianguo Zhao & Wei Li

Authors
  1. Yanjie Ma
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  9. Chao Liu
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Contributions

All authors contributed to the study conception and design. YM, BW, and YC performed most of the experimental work of the study, analyzed data, and wrote the manuscript. SM, LW, Tingting Han, XL, and FY performed part of the experiments. WL, JZ, and CL designed the experiments, supervised the whole project, and revised the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chao Liu, Jianguo Zhao or Wei Li.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All the animal experiments were approved by the Animal Research Panel of the Committee on Research Practice of the University of the Chinese Academy of Sciences (Approval number: IOZ20180012). All of the animal experiments were performed according to approved institutional animal care and use committee (IACUC) protocols (#08–133) of the Institute of Zoology, Chinese Academy of Sciences. All the 8-week male mice were sacrificed by cervical dislocation before testes collection.

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Informed consent was obtained from all individual participants included in the study.

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Ma, Y., Wu, B., Chen, Y. et al. CCDC146 is required for sperm flagellum biogenesis and male fertility in mice. Cell. Mol. Life Sci. 81, 1 (2024). https://doi.org/10.1007/s00018-023-05025-x

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