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Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia. Hum Mol Genet

Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan.
Human Molecular Genetics (Impact Factor: 6.68). 10/2008; 17(20):3204-11. DOI: 10.1093/hmg/ddn216
Source: PubMed

ABSTRACT Ribosomes are responsible for protein synthesis in all cells. Ribosomal protein S19 (RPS19) is one of the 79 ribosomal proteins (RPs) in vertebrates. Heterozygous mutations in RPS19 have been identified in 25% of patients with Diamond-Blackfan anemia (DBA), but the relationship between RPS19 mutations and the pure red-cell aplasia of DBA is unclear. In this study, we developed an RPS19-deficient zebrafish by knocking down rps19 using a Morpholino antisense oligo. The RPS19-deficient animals showed a dramatic decrease in blood cells as well as deformities in the head and tail regions at early developmental stages. These phenotypes were rescued by injection of zebrafish rps19 mRNA, but not by injection of rps19 mRNAs with mutations that have been identified in DBA patients. Our results indicate that rps19 is essential for hematopoietic differentiation during early embryogenesis. The effects were specific to rps19, but knocking down the genes for three other RPs, rpl35, rpl35a and rplp2, produced similar phenotypes, suggesting that these genes might have a common function in zebrafish erythropoiesis. The RPS19-deficient zebrafish will provide a valuable tool for investigating the molecular mechanisms of DBA development in humans.

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    • "These improvements occur apart from the deficits shown in ribosome biogenesis, which suggests that Tp53 mediated cell cycle arrest is the primary pathological mechanism in mice affected with TCS (Jones et al., 2008). DBA is a disease caused by mutations in any one of several ribosomal proteins, such as RPL15, RPL26, RPL35, RPL35a, RPLP2, RPS14, and RPS19, which lead to an imbalance between rRNA and ribosomal protein levels during construction of the ribosome (Uechi et al., 2008; Devlin et al., 2010; Horos and von Lindern, 2012; Landowski et al., 2013). Eventually, altered ribosome biosynthesis and the resultant accumulation of free ribosomal proteins leads to the stabilization and enrichment of Tp53, decreased proliferation, and increased apoptosis in a variety of tissues (Horos and von Lindern, 2012). "
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    ABSTRACT: Neural crest cells (NCCs) are a transient, migratory cell population, which originates during neurulation at the neural folds and contributes to the majority of tissues, including the mesenchymal structures of the craniofacial skeleton. The deregulation of the complex developmental processes that guide migration, proliferation, and differentiation of NCCs may result in a wide range of pathological conditions grouped together as neurocristopathies. Recently, due to their multipotent properties neural crest stem cells have received considerable attention as a possible source for stem cell based regenerative therapies. This exciting prospect underlines the need to further explore the developmental programs that guide NCC differentiation. This review explores the particular importance of ribosome biogenesis defects in this context since a specific interface between ribosomopathies and neurocristopathies exists as evidenced by disorders such as Treacher-Collins-Franceschetti syndrome (TCS) and Diamond-Blackfan anemia (DBA).
    Frontiers in Physiology 02/2014; 5:26. DOI:10.3389/fphys.2014.00026 · 3.50 Impact Factor
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    • "In addition , our earlier data indicated that maturation and proliferation of cells in the erythroid lineage , but not vascular and myeloid lineages , are specifically affected in rps19 morphants ( Uechi et al , 2008 ) . Furthermore , the expression pattern of gata1 , an early erythroid marker , was normal in rps19 morphants , indicating that the loss of RPS19 does not disrupt early erythropoiesis in zebrafish ( Uechi et al , 2008 ) . Studies using haematopoietic cell lines and bone marrow cells from DBA patients have demonstrated that the loss of RPS19 induces a TP53 - mediated apoptotic response . "
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    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.
    British Journal of Haematology 03/2011; 152(5):648-54. DOI:10.1111/j.1365-2141.2010.08535.x · 4.96 Impact Factor
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    • "Similar phenotypes are observed when the expression of other ribosomal proteins is lost. The knock-down of RPL35, RPL35a, and RPLP2 in zebrafish leads to erythroid failure and malformations [24], while the loss of RPL11 only leads to alteration of embryonic development [26]. These data highlight an important role for ribosomal proteins not only during erythropoiesis but also for proper organ development. "
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    ABSTRACT: Diamond-Blackfan anemia (DBA) is a rare, pure red-cell aplasia that presents during infancy. Approximately 40% of cases are associated with other congenital defects, particularly malformations of the upper limb or craniofacial region. Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation. Moreover, mutations in other ribosomal protein coding genes account for about 25% of other DBA cases. Recently, the analysis of mice from which the gene coding for the heme exporter Feline Leukemia Virus subgroup C Receptor (FLVCR1) is deleted suggested that this gene may be involved in the pathogenesis of DBA. FLVCR1-null mice show a phenotype resembling that of DBA patients, including erythroid failure and malformations. Interestingly, some DBA patients have disease linkage to chromosome 1q31, where FLVCR1 is mapped. Moreover, it has been reported that cells from DBA patients express alternatively spliced isoforms of FLVCR1 which encode non-functional proteins. Herein, we review the known roles of RPS19 and FLVCR1 in ribosome function and heme metabolism respectively, and discuss how the deficiency of a ribosomal protein or of a heme exporter may result in the same phenotype.
    Advances in Hematology 05/2010; 2010:790632. DOI:10.1155/2010/790632
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