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

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

机构地区：[1]Department of Pediatric Cardiology,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [2]Department of Cardiovascular Medicine,Heart Failure Center,Ruijin Hospital,Ruijin Hospital Lu Wan Branch,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [3]Scientific Research Center,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China [4]Department of Pediatric Cardiology,Shanghai Children's Medical Center,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China

出　　处：《Journal of Genetics and Genomics》2024年第9期934-946,共13页遗传学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81970264).

摘　　要：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 inα-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.

关 键 词：Left-right axis CILIA WES Laterality defects ZEBRAFISH CCDC141 

分 类 号：Q95[生物学—动物学]