Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia

Hidetsugu Torihara, Tamayo Uechi, Anirban Chakraborty, Minori Shinya, Noriyoshi Sakai, Naoya Kenmochi

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Diamond-Blackfan anaemia (DBA) is a cancer-prone genetic disorder characterized by pure red-cell aplasia and associated physical deformities. The ribosomal protein S19 gene (RPS19) is the most frequently mutated gene in DBA (∼25%). TP53-mediated cell cycle arrest and/or apoptosis in erythroid cells have been suggested to be major factors for DBA development, but it is not clear why mutations in the ubiquitously expressed RPS19 gene specifically affect erythropoiesis. Previously, we showed that RPS19 deficiency in zebrafish recapitulates the erythropoietic and developmental phenotypes of DBA, including defective erythropoiesis with severe anaemia. In this study, we analysed the simultaneous loss-of-function of RPS19 and Tp53 in zebrafish to investigate the role of Tp53 in the erythroid and morphological defects associated with RPS19 deficiency. Co-inhibition of Tp53 activity rescued the morphological abnormalities, but did not alleviate erythroid aplasia in RPS19-deficient zebrafish. In addition, knockdown of two other RP genes, rps3a and rpl36a, which result in severe morphological abnormalities but only mild erythroid defects, also elicited an activated Tp53 response. These results suggest that a Tp53-independent but RPS19-dependent pathway could be responsible for defective erythropoiesis in RPS19-deficient zebrafish.

Original languageEnglish
Pages (from-to)648-654
Number of pages7
JournalBritish Journal of Haematology
Volume152
Issue number5
DOIs
Publication statusPublished - 2011 Mar 1
Externally publishedYes

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Keywords

  • Diamond-Blackfan anaemia
  • Erythropoiesis
  • Ribosomal protein S19
  • Tp53
  • Zebrafish

ASJC Scopus subject areas

  • Hematology

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