Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia
Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia
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DOI：
10.1093/hmg/ddn216
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发表时间：
2008-10-15
影响因子：
3.5
通讯作者：
Kenmochi, Naoya
中科院分区：
文献类型：
--
作者：
Uechi, Tamayo;Nakajima, Yukari;Kenmochi, Naoya
核糖体负责所有细胞中的蛋白质合成。核糖体蛋白S19 （RPS19）是脊椎动物体内79种核糖体蛋白之一。在25%的Diamond-Blackfan贫血（DBA）患者中发现了RPS19的杂合突变，但RPS19突变与DBA的纯红细胞发育不全之间的关系尚不清楚。在这项研究中，我们利用Morpholino反义寡核苷酸敲除rps19，从而培育出rps19缺陷的斑马鱼。缺乏rps19的动物在早期发育阶段表现出血细胞的急剧减少以及头部和尾部区域的畸形。这些表型可以通过注射斑马鱼rps19 mRNA来恢复，但不能通过注射在DBA患者中发现的突变的rps19 mRNA来恢复。我们的研究结果表明，rps19在早期胚胎发生过程中对造血分化至关重要。这种影响仅针对rps19，但敲除另外三种rpl35、rpl35a和rplp2的基因会产生类似的表型，这表明这些基因可能在斑马鱼的红细胞生成中具有共同的功能。rps19缺陷斑马鱼将为研究人类DBA发展的分子机制提供有价值的工具。
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.