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Int J Biochem Cell Biol. 2014 Apr;49:1-7. doi: 10.1016/j.biocel.2014.01.006. Epub 2014 Jan 11.

Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish.

Author information

1
Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.
2
Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan. Electronic address: kenmochi@med.miyazaki-u.ac.jp.

Erratum in

  • Int J Biochem Cell Biol. 2014 Oct;55:350.

Abstract

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.

KEYWORDS:

DBA; Ribosomal proteins; Ribosomopathy; Tp53; Zebrafish

PMID:
24417973
DOI:
10.1016/j.biocel.2014.01.006
[Indexed for MEDLINE]

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