PUBLICATION
ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish
- Authors
- Wang, P., Shi, W., Liu, S., Shi, Y., Jiang, X., Li, F., Chen, S., Sun, K., Xu, R.
- ID
- ZDB-PUB-240727-7
- Date
- 2024
- Source
- Journal of genetics and genomics = Yi chuan xue bao 51(9): 934-946 (Journal)
- Registered Authors
- Keywords
- WES, birth defects, cilia, left-right, zebrafish
- MeSH Terms
-
- Animals
- Tubulin/genetics
- Tubulin/metabolism
- Humans
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mutation/genetics
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental/genetics
- Cilia*/genetics
- Cilia*/metabolism
- Cilia*/pathology
- Zebrafish*/genetics
- Signal Transduction/genetics
- Body Patterning*/genetics
- Embryonic Development/genetics
- PubMed
- 39047937 Full text @ J. Genet. Genomics
Citation
Wang, P., Shi, W., Liu, S., Shi, Y., Jiang, X., Li, F., Chen, S., Sun, K., Xu, R. (2024) ccdc141 is required for left-right axis development by regulating cilia formation in the Kupffer's vesicle of zebrafish. Journal of genetics and genomics = Yi chuan xue bao. 51(9):934-946.
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 (KV) 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. Thus, we identify CCDC141 as a causative gene for lateral defects.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping