NCK-associated protein 1 like (nckap1l) minor splice variant regulates intrahepatic biliary network morphogenesis

Impaired formation of the intrahepatic biliary network leads to cholestatic liver diseases, which are frequently associated with autoimmune disorders. Using a chemical mutagenesis strategy in zebrafish combined with computational network analysis, we screened for novel genes involved in intrahepatic...

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Bibliographic Details
Published in:PLoS genetics 2021-03, Vol.17 (3), p.e1009402
Main Authors: Ghaffari, Kimia, Pierce, Lain X, Roufaeil, Maria, Gibson, Isabel, Tae, Kevin, Sahoo, Saswat, Cantrell, James R, Andersson, Olov, Lau, Jasmine, Sakaguchi, Takuya F
Format: Article
Language:English
Subjects:
Alternative splicing
Analysis
Bile ducts
Biliary tract
Biology and Life Sciences
Computer and Information Sciences
Computer applications
Control
Cyclin-dependent kinase 5
Cyclin-dependent kinases
Disease
Ethyl nitrosourea
Gene mutations
Genes
Genetic aspects
Genetic screening
Immune system
Isoforms
Kinases
Larvae
Liver
Medicin och hälsovetenskap
Medicine and Health Sciences
Morphogenesis
mRNA
Mutagenesis
Mutants
Mutation
Pathogenesis
Personal appearance
Phenotypes
Physiological aspects
Proteins
Research and Analysis Methods
RNA splicing
Siblings
Standard deviation
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Summary:Impaired formation of the intrahepatic biliary network leads to cholestatic liver diseases, which are frequently associated with autoimmune disorders. Using a chemical mutagenesis strategy in zebrafish combined with computational network analysis, we screened for novel genes involved in intrahepatic biliary network formation. We positionally cloned a mutation in the nckap1l gene, which encodes a cytoplasmic adaptor protein for the WAVE regulatory complex. The mutation is located in the last exon after the stop codon of the primary splice isoform, only disrupting a previously unannotated minor splice isoform, which indicates that the minor splice isoform is responsible for the intrahepatic biliary network phenotype. CRISPR/Cas9-mediated nckap1l deletion, which disrupts both the primary and minor isoforms, showed the same defects. In the liver of nckap1l mutant larvae, WAVE regulatory complex component proteins are degraded specifically in biliary epithelial cells, which line the intrahepatic biliary network, thus disrupting the actin organization of these cells. We further show that nckap1l genetically interacts with the Cdk5 pathway in biliary epithelial cells. These data together indicate that although nckap1l was previously considered to be a hematopoietic cell lineage-specific protein, its minor splice isoform acts in biliary epithelial cells to regulate intrahepatic biliary network formation.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1009402