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

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

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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 hu-man 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,ccdc1 41-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 axisCiliaWESLaterality defectsZebrafishCCDC141

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

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Department of Pediatric Cardiology,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China

Department of Cardiovascular Medicine,Heart Failure Center,Ruijin Hospital,Ruijin Hospital Lu Wan Branch,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Scientific Research Center,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China

Department of Pediatric Cardiology,Shanghai Children's Medical Center,Shanghai Jiaotong University School of Medicine,Shanghai 200127,China

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2024

10.1016/j.jgg.2024.07.014

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(9)