Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia
Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia
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DOI：
10.1111/j.1365-2141.2010.08535.x
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发表时间：
2011-03-01
影响因子：
6.5
通讯作者：
Kenmochi, Naoya
中科院分区：
文献类型：
--
作者：
Torihara, Hidetsugu;Uechi, Tamayo;Kenmochi, Naoya
Diamond-Blackfan贫血（DBA）是一种易发癌症的遗传性疾病，其特征是纯粹的红细胞发育不全和相关的身体畸形。核糖体蛋白S19基因（RPS19）是DBA中最常见的突变基因（约25%）。tp53介导的红细胞细胞周期阻滞和/或凋亡已被认为是DBA发展的主要因素，但目前尚不清楚为什么普遍表达的RPS19基因突变会特异性影响红细胞生成。之前，我们发现斑马鱼的RPS19缺陷重现了DBA的红细胞生成和发育表型，包括严重贫血的红细胞生成缺陷。在这项研究中，我们分析了斑马鱼中RPS19和Tp53的同时功能丧失，以研究Tp53在红系中的作用以及与RPS19缺乏相关的形态学缺陷。Tp53活性的共同抑制挽救了rps19缺陷斑马鱼的形态异常，但没有减轻红系发育不全。此外，rps3a和rpl36a这两个RP基因的敲低也会导致严重的形态学异常，但只有轻微的红系缺陷，也会引起激活的Tp53反应。这些结果表明，一种不依赖tp53但依赖rps19的途径可能是rps19缺陷斑马鱼红细胞生成缺陷的原因。
P>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 (similar to 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.