Mutations in several ribosomal proteins (RPs) lead to Diamond-Blackfan anemia (DBA), a syndrome characterized by defective erythropoiesis, congenital anomalies, and increased frequency of cancer. RPS19 is the most frequently mutated RP in DBA. RPS19 deficiency impairs ribosomal biogenesis, but how this leads to DBA or cancer remains unknown. We have found that rps19 deficiency in zebrafish results in hematopoietic and developmental abnormalities resembling DBA. Our data suggest that the rps19-deficient phenotype is mediated by dysregulation of deltaNp63 and p53. During gastrulation, deltaNp63 is required for specification of nonneural ectoderm and its up-regulation suppresses neural differentiation, thus contributing to brain/ craniofacial defects. In rps19-deficient embryos, deltaNp63 is induced in erythroid progenitors and may contribute to blood defects. We have shown that suppression of p53 and deltaNp63 alleviates the rps19-deficient phenotypes. Mutations in other ribosomal proteins, such as S8, S11, and S18, also lead to up-regulation of p53 pathway, suggesting it is a common response to ribosomal protein deficiency. Our finding provides new insights into pathogenesis of DBA. Ribosomal stress syndromes represent a broader spectrum of human congenital diseases caused by genotoxic stress; therefore, imbalance of p53 family members may become a new target for therapeutics. (Blood. 2008;112: 5228-5237) IntroductionThe precise control of ribosome biogenesis and translation is vital for cell survival. Cell growth and proliferation as well as responses to genotoxic stress depend on ribosomal activity. Defective ribosomal synthesis has been associated with bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), dyskeratosis congenita, and Shwachman-BodianDiamond syndrome. 1 DBA is a congenital syndrome characterized by anemia, bone marrow erythroblastopenia, and increased incidence of cancer. [1][2][3] Anemia is often accompanied by growth retardation and various malformations. Ribosomal protein S19 (RPS19) is mutated in one fourth of patients 4 ; mutations of other ribosomal proteins can also lead to DBA. 5,6 Red blood cells of DBA patients manifest altered transcription, translation, and activated apoptotic pathways. 7-9 RPS19 is necessary for ribosome biosynthesis. Certain RPS19 mutations affect its structure and assembly into the ribosome. 10,11 In yeast and human, deficiency of RPS19 impairs the processing of 18S rRNA and aberrant pre-40S particles are retained in the nucleolus. [12][13][14] Nucleolar organization is distorted in skin fibroblasts in all DBA patients regardless of the presence of RPS19 mutations, 13 suggesting that defect in ribosome biogenesis is a general feature of DBA. The nucleolus can act as a stress sensor; its disruption mediated p53 up-regulation. 15 Mutations in other proteins participating in ribosome biogenesis lead to p53 up-regulation. [16][17][18] Haploinsufficiency of RPS6 and RPL22 also leads to activation of p53. 19,20 Hence, we hypothesized that up-regulation o...
Defects in ribosome biogenesis are associated with a group of diseases called the ribosomopathies, of which Diamond-Blackfan anemia (DBA) is the most studied. Ribosomes are composed of ribosomal proteins (RPs) and ribosomal RNA (rRNA). RPs and multiple other factors are necessary for the processing of pre-rRNA, the assembly of ribosomal subunits, their export to the cytoplasm and for the final assembly of subunits into a ribosome. Haploinsufficiency of certain RPs causes DBA, whereas mutations in other factors cause various other ribosomopathies. Despite the general nature of their underlying defects, the clinical manifestations of ribosomopathies differ. In DBA, for example, red blood cell pathology is especially evident. In addition, individuals with DBA often have malformations of limbs, the face and various organs, and also have an increased risk of cancer. Common features shared among human DBA and animal models have emerged, such as small body size, eye defects, duplication or overgrowth of ectoderm-derived structures, and hematopoietic defects. Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways. The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies. Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.
Summary 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.
The zebrafish, with its transparent free-living embryo, is a useful organism for investigating early stages in lymphopoiesis. Previously, we showed that T cells differentiate in the thymus by day 4, but no sites for B cell differentiation were seen until 3 weeks. We report here that on day 4, we detect rearrangements of genes encoding B cell receptors in DNA extracted from whole fish. Also by day 4, rag1 transcripts are seen in the pancreas, an organ not previously associated with lymphopoiesis; by day 10, Ig transcripts are detected here. Thus, in zebrafish, the pancreas assumes the role of both the liver in fetal mice and the spleen in neonatal mice.
Key Points• GATA1 is downregulated in RPS19-deficient cells and zebrafish through upregulation of p53, TNF-a, and p38 MAPK.• Treatment of rps19-deficient zebrafish with the TNF-a inhibitor etanercept rescues their erythroid and developmental defects.Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-a (TNF-a) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-a or p53. The anemia phenotype in rps19-deficient zebrafish was reversed by treatment with the TNF-a inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53-dependent increase in TNF-a, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA. (Blood. 2014;124(25):3791-3798)
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