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Alliance"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:p>\n                    Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman\u2013Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in\n                    <jats:italic>SBDS<\/jats:italic>\n                    , which encodes a ribosome assembly factor. Some individuals express a missense mutation,\n                    <jats:italic>SBDS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>R126T<\/jats:italic>\n                    <\/jats:sup>\n                    , along with the common K62X mutation. We reported that the\n                    <jats:italic>sbds<\/jats:italic>\n                    -null zebrafish phenocopies much of SDS. We further showed activation of Tp53-dependent pathways before the fish died during the larval stage. Here, we expressed\n                    <jats:italic>SBDS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>R126T<\/jats:italic>\n                    <\/jats:sup>\n                    as a transgene in the\n                    <jats:italic>sbds<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    background. We showed that one copy of the\n                    <jats:italic>SBDS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>R126T<\/jats:italic>\n                    <\/jats:sup>\n                    transgene permitted the establishment of maternal zygotic\n                    <jats:italic>sbds<\/jats:italic>\n                    -null fish which produced defective embryos with\n                    <jats:italic>cdkn1a<\/jats:italic>\n                    up-regulation, a Tp53 target involved in cell cycle arrest. None survived beyond 3 dpf. However, two copies of the transgene resulted in normal development and lifespan. Surprisingly, neutropenia persisted. The surviving fish displayed suppression of female sex differentiation, a stress response in zebrafish. To evaluate the role of Tp53 in the pathogenesis of\n                    <jats:italic>sbds<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    fish phenotype, we bred the fish with a DNA binding deficient allele,\n                    <jats:italic>tp53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M214K<\/jats:italic>\n                    <\/jats:sup>\n                    . Expression of the loss-of-function\n                    <jats:italic>tp53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M214K<\/jats:italic>\n                    <\/jats:sup>\n                    did not rescue neutropenia or survival in\n                    <jats:italic>sbds<\/jats:italic>\n                    -null zebrafish. Increased expression of\n                    <jats:italic>cdkn1a<\/jats:italic>\n                    was abrogated in the\n                    <jats:italic>tp53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>M214K\/M214K<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>;sbds<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    fish. We conclude that the amount of SBDS\n                    <jats:sup>R126T<\/jats:sup>\n                    protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the\n                    <jats:italic>sbds<\/jats:italic>\n                    -null background, and\n                    <jats:italic>cdkn1a<\/jats:italic>\n                    up-regulation was dependent on WT\n                    <jats:italic>tp53<\/jats:italic>\n                    . We hypothesize that additional pathways are involved in the pathophysiology of SDS.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202201856","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:20:20Z","timestamp":1696944020000},"page":"e202201856","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["SBDS\n                    <sup>R126T<\/sup>\n                    rescues survival of\n                    <i>sbds<\/i>\n                    <sup>\n                      <i>\u2212\/\u2212<\/i>\n                    <\/sup>\n                    zebrafish in a dose-dependent manner independently of Tp53"],"prefix":"10.26508","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-7945","authenticated-orcid":true,"given":"Usua","family":"Oyarbide","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Cancer Biology and Pediatrics, Cleveland Clinic","place":[", Cleveland, OH, 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. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4919-8040","authenticated-orcid":true,"given":"Morgan","family":"Staton","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Cancer Biology and Pediatrics, Cleveland Clinic","place":[", Cleveland, OH, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Snyderman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Cancer Biology and Pediatrics, Cleveland Clinic","place":[", Cleveland, OH, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adya","family":"Sapra","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03xjacd83","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Cancer Biology and Pediatrics, Cleveland Clinic","place":[", Cleveland, OH, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3006-2742","authenticated-orcid":false,"given":"Eliezer","family":"Calo","sequence":"additional","affiliation":[{"name":"Department of Biology and David H. 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