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ZFIN ID: ZDB-PUB-140317-34
Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish
Yadav, G.V., Chakraborty, A., Uechi, T., and Kenmochi, N.
Date: 2014
Source: The international journal of biochemistry & cell biology   49: 1-7 (Journal)
Registered Authors: Kenmochi, Naoya, Uechi, Tamayo, Yadav, Gnaneshwar
Keywords: none
MeSH Terms:
  • Anemia, Diamond-Blackfan/genetics
  • Anemia, Diamond-Blackfan/metabolism
  • Animals
  • Arginine/pharmacology
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Erythrocyte Count
  • Erythroid Cells/drug effects
  • Erythroid Cells/metabolism
  • Erythropoiesis/genetics*
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Humans
  • Leucine/pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Proteins/deficiency
  • Ribosomal Proteins/genetics*
  • Ribosomes/genetics
  • Ribosomes/metabolism
  • Sirolimus/pharmacology
  • Tumor Suppressor Protein p53/genetics*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 24417973 Full text @ Int. J. Biochem. Cell Biol.

Diamond-Blackfan anemia is an inherited genetic disease caused by mutations in ribosomal protein genes. The disease is characterized by bone marrow failure, congenital anomalies, and a severe erythroid defect. The activation of the TP53 pathway has been suggested to be critical for the pathophysiology of Diamond-Blackfan anemia. While this pathway plays a role in the morphological defects that associate with ribosomal protein loss-of-function in animal models, its role in the erythroid defects has not been clearly established. To understand the specificity of erythroid defects in Diamond-Blackfan anemia, we knocked down five RP genes (two Diamond-Blackfan anemia-associated and three non-Diamond-Blackfan anemia-associated) in zebrafish and analyzed the effects on the developmental and erythroid phenotypes in the presence and absence of Tp53. The co-inhibition of Tp53 activity rescued the morphological deformities but did not alleviate the erythroid aplasia indicating that ribosomal protein deficiency causes erythroid failure in a Tp53-independent manner. Interestingly, treatment with L-Leucine or L-Arginine, amino acids that augment mRNA translation via mTOR pathway, rescued the morphological defects and resulted in a substantial recovery of erythroid cells. Our results suggest that altered translation because of impaired ribosome function could be responsible for the morphological and erythroid defects in ribosomal protein-deficient zebrafish.