The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.
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Authors
Bielczyk-Maczyńska, Ewa
Lam Hung, Laure
Ferreira, Lauren
Fleischmann, Tobias
Weis, Félix
Fernández-Pevida, Antonio
Harvey, Steven A
Wali, Neha
Stemple, Derek L
Publication Date
2015-12Journal Title
PLoS Genet
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Volume
11
Number
e1005677
Language
English
Type
Article
Metadata
Show full item recordCitation
Bielczyk-Maczyńska, E., Lam Hung, L., Ferreira, L., Fleischmann, T., Weis, F., Fernández-Pevida, A., Harvey, S. A., et al. (2015). The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.. PLoS Genet, 11 (e1005677) https://doi.org/10.1371/journal.pgen.1005677
Abstract
Ribosome biogenesis is a ubiquitous and essential process in cells. Defects in ribosome biogenesis and function result in a group of human disorders, collectively known as ribosomopathies. In this study, we describe a zebrafish mutant with a loss-of-function mutation in nol9, a gene that encodes a non-ribosomal protein involved in rRNA processing. nol9sa1022/sa1022 mutants have a defect in 28S rRNA processing. The nol9sa1022/sa1022 larvae display hypoplastic pancreas, liver and intestine and have decreased numbers of hematopoietic stem and progenitor cells (HSPCs), as well as definitive erythrocytes and lymphocytes. In addition, ultrastructural analysis revealed signs of pathological processes occurring in endothelial cells of the caudal vein, emphasizing the complexity of the phenotype observed in nol9sa1022/sa1022 larvae. We further show that both the pancreatic and hematopoietic deficiencies in nol9sa1022/sa1022 embryos were due to impaired cell proliferation of respective progenitor cells. Interestingly, genetic loss of Tp53 rescued the HSPCs but not the pancreatic defects. In contrast, activation of mRNA translation via the mTOR pathway by L-Leucine treatment did not revert the erythroid or pancreatic defects. Together, we present the nol9sa1022/sa1022 mutant, a novel zebrafish ribosomopathy model, which recapitulates key human disease characteristics. The use of this genetically tractable model will enhance our understanding of the tissue-specific mechanisms following impaired ribosome biogenesis in the context of an intact vertebrate.
Sponsorship
The study was supported by Cancer Research UK (grant number C45041/A14953 to AC and LF), Wellcome Trust (grants number 084183/Z/07/Z to EBM and number 098051 to DLS and LLH), Specialist Programme from Bloodwise [12048], the Medical Research Council [MC_U105161083] and Ted’s Gang (to AJW), a Wellcome Trust strategic award to the Cambridge Institute for Medal Research [100140] and the Cambridge NIHR Biomedical Research Centre (to AJW and AC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funder references
Wellcome Trust (084183/Z/07/Z)
Medical Research Council (MR/L003368/1)
Bloodwise (15035)
Leukaemia & Lymphoma Research (12048)
Leukaemia & Lymphoma Research (11027)
Leukaemia & Lymphoma Research (8003)
Wellcome Trust (100140/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1371/journal.pgen.1005677
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252447
Rights
Creative Commons Attribution 4.0 International Licens
Licence URL: http://creativecommons.org/licenses/by/4.0/
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