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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 

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.

Description

Keywords

Animals, Disease Models, Animal, Hematopoiesis, Hematopoietic Stem Cells, Humans, Morphogenesis, Pancreas, Polynucleotide 5'-Hydroxyl-Kinase, RNA, Ribosomal, 28S, Ribosomes, Tumor Suppressor Protein p53, Zebrafish

Journal Title

PLoS Genet

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

11

Publisher

Public Library of Science (PLoS)
Sponsorship
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)
Wellcome Trust (097922/Z/11/B)
Cancer Research Uk (None)
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.