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Biallelic mutations in\n                    <jats:italic>SBDS<\/jats:italic>\n                    , which encodes a ribosome maturation factor, are found in 90% of SDS cases.\n                    <jats:italic>\n                      Sbds\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice are embryonic lethal. Using CRISPR\/Cas9 editing, we created\n                    <jats:italic>sbds-<\/jats:italic>\n                    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\n                    <jats:italic>tp53<\/jats:italic>\n                    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,\n                    <jats:italic>cdkn1a<\/jats:italic>\n                    and\n                    <jats:italic>ccng1<\/jats:italic>\n                    , and apoptosis,\n                    <jats:italic>puma<\/jats:italic>\n                    and\n                    <jats:italic>mdm2<\/jats:italic>\n                    . 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 \u2014 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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.134309","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T12:03:40Z","timestamp":1596715420000},"source":"Crossref","is-referenced-by-count":21,"title":["Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-7945","authenticated-orcid":true,"given":"Usua","family":"Oyarbide","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, Immunology, and Human and Molecular Genetics, Children\u2019s Hospital of Richmond and Massey Cancer Center at Virginia Commonwealth University, Richmond, Virginia, USA."},{"name":"Department of Pediatrics, Stanley Manne Children\u2019s Research Institute, Northwestern University School of Medicine, Chicago, Illinois, USA."},{"name":"Departments of Pediatrics, Cancer Biology, and Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4036-9772","authenticated-orcid":true,"given":"Arish N.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Biology and David H. 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