Ribosomal protein L11 mutation in zebrafish leads to haematopoietic and metabolic defects.
Mutations in ribosomal proteins are associated with a congenital syndrome, Diamond-Blackfan anaemia (DBA), manifested by red blood cell aplasia, developmental abnormalities and increased risk of malignancy. Recent studies suggest the involvement of p53 activation in DBA. However, which pathways are involved and how they contribute to the DBA phenotype remains unknown. Here we show that a zebrafish mutant for the rpl11 gene had defects both in the development of haematopoietic stem cells (HSCs) and maintenance of erythroid cells. The molecular signature of the mutant included upregulation of p53 target genes and global changes in metabolism. The changes in several pathways may affect haematopoiesis including upregulation of pro-apoptotic and cell cycle arrest genes, suppression of glycolysis, downregulation of biosynthesis and dysregulation of cytoskeleton. Each of these pathways has been individually implicated in haematological diseases. Inhibition of p53 partially rescued haematopoiesis in the mutant. Altogether, we propose that the unique phenotype of DBA is a sum of several abnormally regulated molecular pathways, mediated by the p53 protein family and p53-independent, which have synergistic impact on haematological and other cellular pathways affected in DBA. Our results provide new insights into the pathogenesis of DBA and point to the potential avenues for therapeutic intervention.
Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, 90095, USA.
Nadia
N
Danilova
Kathleen M
KM
Sakamoto
Shuo
S
Lin
D029503:Anemia, Diamond-Blackfan / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006133:Growth Substances / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
D005938:Glucocorticoids; D006133:Growth Substances; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D003907:Dexamethasone