title: The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish.
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.
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.|NHS Blood and Transplant, Cambridge, United Kingdom.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bielczyk-Maczyńska
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Laure
authors.initials: L
authors.lastname: Lam Hung
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Lauren
authors.initials: L
authors.lastname: Ferreira
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fleischmann
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Félix
authors.initials: F
authors.lastname: Weis
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Pevida
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Harvey
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Neha
authors.initials: N
authors.lastname: Wali
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Warren
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Cvejic
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D009024:Morphogenesis / Q000235:genetics*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000096:biosynthesis* / Q000235:genetics; D012339:RNA, Ribosomal, 28S / Q000235:genetics; D012270:Ribosomes / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015027:Zebrafish
chemical_list: D012339:RNA, Ribosomal, 28S; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011116:Polynucleotide 5'-Hydroxyl-Kinase; C554920:NOL9 protein, human