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Updated: Jul 9, 2025
Cytological Analysis of Spermatogenesis: Live and Fixed Preparations of Drosophila Testes
Published on: January 20, 2014
CCDC146 is required for sperm flagellum biogenesis and male fertility in mice
Yanjie Ma1,2,3, Bingbing Wu1,2,3, Yinghong Chen1,2,3
1State 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.
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.
Insights
The coiled-coil domain containing 146 (CCDC146) gene is crucial for sperm flagellum formation and male fertility. Its deficiency causes infertility and Multiple Morphological Abnormalities of the Flagella (MMAF)-like phenotypes.
Area of Science:
- Reproductive Biology
- Molecular Genetics
- Cell Biology
Background:
- Multiple Morphological Abnormalities of the Flagella (MMAF) is a severe cause of male infertility with poorly understood mechanisms.
- Previous research suggested a link between Ccdc38 deficiency and MMAF.
- Identifying interacting partners of CCDC38 is key to understanding MMAF pathogenesis.
Purpose of the Study:
- To investigate the role of coiled-coil domain containing 146 (CCDC146) in male fertility and spermiogenesis.
- To elucidate the molecular mechanisms underlying CCDC146's function in flagellum biogenesis.
- To explore the potential association of CCDC146 mutations with MMAF.
Main Methods:
- Gene knockout in mice to assess fertility and spermiogenesis.
- Protein-protein interaction studies (co-immunoprecipitation, yeast two-hybrid).
- Western blotting to analyze protein expression levels.
- Molecular modeling to predict and validate protein interactions.
Main Results:
- CCDC146 is predominantly expressed in testes and its knockout causes complete male infertility.
- Ccdc146 knockout leads to defects in sperm flagellum and manchette organization, resulting in an MMAF-like phenotype.
- CCDC146 interacts with CCDC38, CCDC42, and intraflagellar transport (IFT) components (IFT88, IFT20), and its absence decreases ODF2, IFT88, and IFT20 protein levels.
Conclusions:
- Testis-specific gene Ccdc146 is essential for sperm flagellum biogenesis and male fertility.
- CCDC146 plays a critical role in organizing flagellar structures, likely through interactions with CCDC38, CCDC42, and IFT machinery.
- Mutations in CCDC146 may contribute to MMAF in patients, highlighting its clinical relevance.
