PUBLICATION

The nuclear gene rpl18 regulates erythroid maturation via JAK2-STAT3 signaling in zebrafish model of Diamond-Blackfan anemia

Authors
Chen, C., Lu, M., Lin, S., Qin, W.
ID
ZDB-PUB-200222-2
Date
2020
Source
Cell Death & Disease   11: 135 (Journal)
Registered Authors
Lin, Shuo, Qing, Wei
Keywords
none
MeSH Terms
  • Anemia, Diamond-Blackfan/blood
  • Anemia, Diamond-Blackfan/drug therapy
  • Anemia, Diamond-Blackfan/enzymology*
  • Anemia, Diamond-Blackfan/genetics
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Erythroid Cells/drug effects
  • Erythroid Cells/enzymology*
  • Erythropoiesis*/drug effects
  • Janus Kinase 2/antagonists & inhibitors
  • Janus Kinase 2/metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors/pharmacology
  • Ribosomal Proteins/genetics
  • Ribosomal Proteins/metabolism*
  • STAT3 Transcription Factor/antagonists & inhibitors
  • STAT3 Transcription Factor/metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/metabolism*
PubMed
32075953 Full text @ Cell Death Dis.
Abstract
Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome, characterized by red blood cell aplasia, developmental abnormalities, and enhanced risk of malignancy. However, the underlying pathogenesis of DBA is yet to be understood. Recently, mutations in the gene encoding ribosomal protein (RP) L18 were identified in DBA patients. RPL18 is a crucial component of the ribosomal large subunit but its role in hematopoiesis remains unknown. To genetically model the ribosomal defect identified in DBA, we generated a rpl18 mutant line in zebrafish, using CRISPR/Cas9 system. Molecular characterization of this mutant line demonstrated that Rpl18 deficiency mirrored the erythroid defects of DBA, namely a lack of mature red blood cells. Rpl18 deficiency caused an increase in p53 activation and JAK2-STAT3 activity. Furthermore, we found inhibitors of JAK2 or STAT3 phosphorylation could rescue anemia in rpl18 mutants. Our research provides a new in vivo model of Rpl18 deficiency and suggests involvement of signal pathway of JAK2-STAT3 in the DBA pathogenesis.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping