Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish
- Authors
- Yadav, G.V., Chakraborty, A., Uechi, T., and Kenmochi, N.
- ID
- ZDB-PUB-140317-34
- 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.