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Cited by 5Pediatric Hepatobiliary Diseases and TreatmentsZebrafish Biomedical Research ApplicationsLiver physiology and pathology

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

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Ghaffari, Kimia, Pierce, Lain X., Roufaeil, Maria, Gibson, Isabel, Tae, Kevin, Sahoo, Saswat, Cantrell, James R., Andersson, Olov +2 more·2021·PLOS Genetics
DOI 10.1371/journal.pgen.1009402PMC PMC8032155
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Abstract

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.

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  • An alternative NCKAP1L splice form is expressed in biliary epithelial cells and promotes intrahepatic biliary tree morphogenesis.

    “A recent report demonstrated expression of an alternative NCKAP1L splice form in biliary epithelial cells promotes intrahepatic biliary tree morphogenesis [51].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [51]

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Cited by

Sorted by citations

Authors
Ghaffari, K., Pierce, L. X., Roufaeil, M., Gibson, I., Tae, K., Sahoo, S., Cantrell, J. R., Andersson, O., Lau, J., & Sakaguchi, T. F.
Affiliations
  • Cleveland Clinic (US)
  • Karolinska Institutet (SE)
Corresponding author
Sakaguchi, Takuya F.
ORCID
Venue
PLOS Genetics
Publisher
Public Library of Science (PLoS)
Published
2021-03-19
Volume
17
Issue
3
Pages
e1009402
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1009402
PMC
PMC8032155
OpenAlex
W3138529367
Cited by
5
References
1
Citations by year
2025: 2 · 2024: 1 · 2022: 2
FWCI
0.70
Type
journal article
Language
en
Update notices
new_version (2021-04-08)
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01 DK103637)
  • Cleveland Digestive Diseases Research Core Center (P30 DK084576)
  • Lerner Research Institute, Cleveland Clinic
  • Cleveland Clinic Liver Tumor Research Center of Excellence Fund
Topics
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
cholangiocytes, WAVE regulatory complex, actin organization, cholestatic liver disease, zebrafish, chemical mutagenesis, positional cloning, CRISPR/Cas9 gene deletion
MeSH terms
Alleles, Animals, Bile Ducts, Intrahepatic, Genetic Testing, Liver, Models, Biological, Morphogenesis, Mutation, Phenotype, Genetic Variation, Zebrafish, Alternative Splicing, Gene Expression Regulation, Developmental, rac1 GTP-Binding Protein, Gene Order, Animals, Genetically Modified, Adaptor Proteins, Signal Transducing, Cyclin-Dependent Kinase 5, Gene Knockdown Techniques, RNA Isoforms

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