NCK-associated protein 1 like (nckap1l) minor splice variant regulates intrahepatic biliary network morphogenesis
Autoři:
Kimia Ghaffari aff001; Lain X. Pierce aff001; Maria Roufaeil aff001; Isabel Gibson aff001; Kevin Tae aff001; Saswat Sahoo aff001; James R. Cantrell aff001; Olov Andersson aff003; Jasmine Lau aff001; Takuya F. Sakaguchi aff001
Působiště autorů:
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
aff001; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America
aff002; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
aff003; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America
aff004
Vyšlo v časopise:
NCK-associated protein 1 like (nckap1l) minor splice variant regulates intrahepatic biliary network morphogenesis. PLoS Genet 17(3): e1009402. doi:10.1371/journal.pgen.1009402
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009402
Souhrn
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.
Klíčová slova:
Actins – Epithelial cells – Genetic networks – Heterozygosity – Larvae – Phenotypes – Zebrafish – Branching morphogenesis
Zdroje
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