Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy
Name
134309.2-20200821191801-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf
Description
Published version
Size
15.67 MB
Format
Adobe PDF
Checksum (MD5)
65a9769547370b636bfb3fd0e5a9dff2
Author(s)
Oyarbide, Usua
Shah, Arish N
Amaya-Mejia, Wilmer
Snyderman, Matthew
Kell, Margaret J
Allende, Daniela S
Calo, Eliezer
Topczewski, Jacek
Corey, Seth J
Date Issued
2020
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
© 2020, Oyarbide et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. 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 postfertilization (dpf). Polysome analysis revealed decreased 80S ribosomes. Homozygous mutant fish developed normally until 15 dpf. Mutant fish subsequently had stunted growth and showed 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 correlated 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 WT fish. Starved WT 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1172/JCI.INSIGHT.134309
