<i>ccdc141</i> is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish

Pengcheng Wang; Wenxiang Shi; Sijie Liu; Yunjing Shi; Xuechao Jiang; Fen Li; Sun Chen; Kun Sun; Rang Xu

doi:10.1016/j.jgg.2024.07.014

Volume 51 Issue 9

Sep. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(9): 934-946

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ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish

doi: 10.1016/j.jgg.2024.07.014

a. Department of Pediatric Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
b. Department of Cardiovascular Medicine, Heart Failure Center, Ruijin Hospital, Ruijin Hospital Lu Wan Branch, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
c. Scientific Research Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
d. Department of Pediatric Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Funds:

This work was supported by the National Natural Science Foundation of China (81970264).

Received Date: 2024-03-22
Accepted Date: 2024-07-17
Rev Recd Date: 2024-07-16

Available Online: 2025-06-06

Publish Date: 2024-07-22

Abstract

Abstract

Laterality is a crucial physiological process intricately linked to the cilium-centrosome complex during embryo development. Defects in the process can result in severe organ mispositioning. Coiled-coil domain containing 141 (CCDC141) has been previously known as a centrosome-related gene, but its role in left-right (LR) asymmetry has not been characterized. In this study, we utilize the zebrafish model and human exome analysis to elucidate the function of ccdc141 in laterality defects. The knockdown of ccdc141 in zebrafish disrupts early LR signaling pathways, cilia function, and Kupffer's vesicle formation. Unlike ccdc141-knockdown embryos exhibiting aberrant LR patterns, ccdc141-null mutants show no apparent abnormality, suggesting a genetic compensation response effect. In parallel, we observe a marked reduction in α-tubulin acetylation levels in the ccdc141 crispants. The treatment with histone deacetylase (HDAC) inhibitors, particularly the HDAC6 inhibitor, rescues the ccdc141 crispant phenotypes. Furthermore, exome analysis of 70 patients with laterality defects reveals an increased burden of CCDC141 mutations, with in-vivo studies verifying the pathogenicity of the patient mutation CCDC141-R123G. Our findings highlight the critical role of ccdc141 in ciliogenesis and demonstrate that CCDC141 mutations lead to abnormal LR patterns, identifying it as a candidate gene for laterality defects.
- Left-right axis,
- Cilia,
- WES,
- Laterality defects,
- Zebrafish,
- CCDC141

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References(51)

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