SBDS rescues survival of zebrafish in a dose-dependent manner independently of Tp53.

Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in , which encodes a ribosome assembly factor. Some individuals express a missense mutation, , along with the common K62X mutation. We reported that the -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 as a transgene in the background. We showed that one copy of the transgene permitted the establishment of maternal zygotic -null fish which produced defective embryos with 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 fish phenotype, we bred the fish with a DNA binding deficient allele, Expression of the loss-of-function did not rescue neutropenia or survival in -null zebrafish. Increased expression of was abrogated in the fish. We conclude that the amount of SBDS protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the -null background, and up-regulation was dependent on WT We hypothesize that additional pathways are involved in the pathophysiology of SDS.