Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy
| العنوان: | Loss of Sbds in zebrafish leads to neutropenia and pancreas and liver atrophy |
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| المؤلفون: | Eliezer Calo, Usua Oyarbide, Arish N Shah, Margaret J. Kell, Wilmer Amaya-Mejia, Matthew Snyderman, Daniela S. Allende, Jacek Topczewski, Seth J. Corey |
| المصدر: | JCI Insight JCI Insight, Vol 5, Iss 17 (2020) |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Cyclin-Dependent Kinase Inhibitor p21, Neutropenia, Cyclin G1, Mutant, Apoptosis, Biology, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Downregulation and upregulation, Polysome, Proto-Oncogene Proteins, medicine, Animals, Zebrafish, Pancreas, P53, Gastroenterology, Nuclear Proteins, Proto-Oncogene Proteins c-mdm2, General Medicine, Hematology, SBDS, Zebrafish Proteins, Zymogen granule, biology.organism_classification, medicine.disease, Molecular biology, Shwachman-Diamond Syndrome, 030104 developmental biology, Liver, 030220 oncology & carcinogenesis, Embryonic development, Medicine, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, Ribosomes, Research Article, Genetic diseases |
| الوصف: | 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. Loss of ribosome maturation factor sbds in the zebrafish phenocopies human Shwachman-Diamond syndrome and is associated with p53 activation, but lethality cannot be rescued by p53 mutation. |
| اللغة: | English |
| تدمد: | 2379-3708 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fe7f0641c0f7f9be7aecb6b77095a45a http://europepmc.org/articles/PMC7526460 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....fe7f0641c0f7f9be7aecb6b77095a45a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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