Essential role of c-myb in definitive hematopoiesis is evolutionarily conserved
Essential role of c-myb in definitive hematopoiesis is evolutionarily conserved
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DOI：
10.1073/pnas.1004640107
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发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Boehm, Thomas
中科院分区：
文献类型：
--
作者：
Soza-Ried, Cristian;Hess, Isabell;Boehm, Thomas
转录因子c-myb已成为脊椎动物造血的关键调节因子之一。在小鼠中，它在血细胞发育的原始阶段是必需的，但在确定的造血作用中是必需的。利用条件性基因敲除策略，最近的研究表明，c-myb是小鼠造血干细胞自我更新所必需的。在这里，我们描述和表征的c-myb突变体在较低的脊椎动物，斑马鱼斑马鱼。在N-乙基-N-亚硝基脲（ENU）诱导的一系列胸腺生成障碍突变体中，发现了c-myb（c-myb（t25127））的隐性功能丧失等位基因。突变等位基因的序列预测在高度保守的DNA结合结构域的重复序列3的DNA识别螺旋中间的错义突变（I181 N）。与在小鼠中的发现一致，原始造血在c-myb突变鱼中不受影响。相比之下，最终造血失败，导致在发育的第20天失去所有血细胞。因此，突变的鱼缺乏淋巴细胞和其他白色和红细胞;尽管如此，它们存活了2-3个月，但表现出发育不良。由于突变鱼存活到成年早期，因此可以直接表明它们的最终造血功能永久消失。因此，我们的研究结果表明，c-myb在造血中的关键作用与哺乳动物相似，并且在脊椎动物进化的早期就已经确立。
The transcription factor c-myb has emerged as one of the key regulators of vertebrate hematopoiesis. In mice, it is dispensable for primitive stages of blood cell development but essentially required for definitive hematopoiesis. Using a conditional knockout strategy, recent studies have indicated that c-myb is required for self-renewal of mouse hematopoietic stem cells. Here, we describe and characterize the c-myb mutant in a lower vertebrate, the zebrafish Danio rerio. The recessive loss-of-function allele of c-myb (c-myb(t25127)) was identified in a collection of N-ethyl-N-nitrosourea (ENU)-induced mutants exhibiting a failure of thymopoiesis. The sequence of the mutant allele predicts a missense mutation (I181N) in the middle of the DNA recognition helix of repeat 3 of the highly conserved DNA binding domain. In keeping with the findings in the mouse, primitive hematopoiesis is not affected in the c-myb mutant fish. By contrast, definitive hematopoiesis fails, resulting in the loss of all blood cells by day 20 of development. Thus, the mutant fish lack lymphocytes and other white and red blood cells; nonetheless, they survive for 2-3 mo but show stunted growth. Because the mutant fish survive into early adulthood, it was possible to directly show that their definitive hematopoiesis is permanently extinguished. Our results, therefore, suggest that the key role of c-myb in definitive hematopoiesis is similar to that in mammals and must have become established early in vertebrate evolution.