title: Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish.
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.
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: Gnaneshwar V
authors.initials: GV
authors.lastname: Yadav
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: Anirban
authors.initials: A
authors.lastname: Chakraborty
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan.
authors.forename: Tamayo
authors.initials: T
authors.lastname: Uechi
authors.affiliation: Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki, Japan. Electronic address: kenmochi@med.miyazaki-u.ac.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Kenmochi
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D004906:Erythrocyte Count; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D007930:Leucine / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D001120:Arginine; D007930:Leucine; D020123:Sirolimus
keywords: DBA; Ribosomal proteins; Ribosomopathy; Tp53; Zebrafish