Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish
Ribosomal protein deficiency causes Tp53-independent erythropoiesis failure in zebrafish
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DOI：
10.1016/j.biocel.2014.01.006
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发表时间：
2014-04-01
影响因子：
4
通讯作者：
Kenmochi, Naoya
中科院分区：
文献类型：
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作者：
Yadav, Gnaneshwar V.;Chakraborty, Anirban;Kenmochi, Naoya
Diamond-Blackfan贫血是一种由核糖体蛋白基因突变引起的遗传性疾病。这种疾病的特征是骨髓衰竭、先天性异常和严重的红细胞缺陷。TP 53通路的激活被认为是Diamond-Blackfan贫血的病理生理学的关键。虽然该途径在动物模型中与核糖体蛋白功能丧失相关的形态学缺陷中起作用，但其在红细胞缺陷中的作用尚未明确确定。为了了解红细胞缺陷的特异性钻石-布莱克凡贫血，我们敲低5 RP基因（2钻石-布莱克凡贫血相关和3个非钻石-布莱克凡贫血相关）在斑马鱼和分析的影响，在TP 53的存在和不存在的发育和红细胞表型。TP 53活性的共抑制挽救了形态学畸形，但没有减轻红系发育不全，表明核糖体蛋白缺乏以TP 53-独立的方式引起红系衰竭。有趣的是，用L-亮氨酸或L-精氨酸（通过mTOR途径增强mRNA翻译的氨基酸）处理挽救了形态缺陷并导致红系细胞的实质性恢复。我们的研究结果表明，由于核糖体功能受损而改变的翻译可能是核糖体蛋白缺陷斑马鱼的形态和红细胞缺陷的原因。(C)2014爱思唯尔有限公司版权所有。
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. (C) 2014 Elsevier Ltd. All rights reserved.