Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy

Oyarbide, U., Shah, A.N., Amaya-Mejia, W., Snyderman, M., Kell, M., Allende, D., Calo, E., Topczewski, J., Corey, S.
JCI insight   5(17): (Journal)
Registered Authors
Corey, Seth, Oyarbide, Usua, Snyderman, Matt, Topczewski, Jacek
Embryonic development, Gastroenterology, Genetic diseases, Hematology, P53
MeSH Terms
  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins/genetics
  • Apoptosis Regulatory Proteins/metabolism
  • Atrophy
  • Cyclin G1/genetics
  • Cyclin G1/metabolism
  • Cyclin-Dependent Kinase Inhibitor p21/genetics
  • Cyclin-Dependent Kinase Inhibitor p21/metabolism
  • Liver/metabolism
  • Liver/pathology
  • Neutropenia/genetics*
  • Neutropenia/metabolism
  • Nuclear Proteins/deficiency
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Pancreas/metabolism
  • Pancreas/pathology
  • Proto-Oncogene Proteins/genetics
  • Proto-Oncogene Proteins/metabolism
  • Proto-Oncogene Proteins c-mdm2/genetics
  • Proto-Oncogene Proteins c-mdm2/metabolism
  • Ribosomes/metabolism
  • Shwachman-Diamond Syndrome/genetics*
  • Shwachman-Diamond Syndrome/metabolism
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
32759502 Full text @ JCI Insight
Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic insufficiency, neutropenia, and skeletal abnormalities. Biallelic mutations in SBDS, which encodes a ribosome maturation factor, are found in 90% of SDS cases. Sbds-/- mice are embryonic lethal. Using CRISPR/Cas9 editing, we created sbds-deficient zebrafish strains. Sbds protein levels progressively decreased and became undetectable at 10 days post fertilization (dpf). Polysome analysis revealed decreased 80S ribosomes. Homozygous mutant fish developed normally until 15 dpf. Mutant fish subsequently have stunted growth and shows signs of atrophy in pancreas, liver, and intestine. In addition, neutropenia occurred by 5 dpf. Upregulation of tp53 mRNA did not occur until 10 dpf and inhibition of proliferation correlating with death by 21 dpf. Transcriptome analysis showed tp53 activation through upregulation of genes involved in cell cycle arrest, cdkn1a and ccng1, and apoptosis, puma and mdm2. However, elimination of Tp53 function did not prevent lethality. Because of growth retardation and atrophy of intestinal epithelia, we studied the effects of starvation on wildtype fish. Starved wildtype fish showed intestinal atrophy, zymogen granule loss, and tp53 upregulation - similar to the mutant phenotype. In addition, there was reduction in neutral lipid storage and ribosomal protein amount, similar to the mutant phenotype. Thus, loss of Sbds in zebrafish phenocopies much of the human disease and is associated with growth arrest and tissue atrophy, particularly of the gastrointestinal system, at the larval stage. A variety of stress responses, some associated with Tp53, contribute to pathophysiology of SDS.
Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes