Zebrafish numb and numblike are involved in primitive erythrocyte differentiation.
Zebrafish numb and numblike are involved in primitive erythrocyte differentiation.
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DOI：
10.1371/journal.pone.0014296
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发表时间：
2010-12-13
期刊：
影响因子：
3.7
通讯作者：
Cotelli F
中科院分区：
文献类型：
--
作者：
Bresciani E;Confalonieri S;Cermenati S;Cimbro S;Foglia E;Beltrame M;Di Fiore PP;Cotelli F
Notch信号传导是一种进化上保守的调控电路，涉及各种发育过程中的细胞命运决定，包括造血干细胞自我更新和血液谱系的分化。已知的Notch活性的内源性抑制剂是Numb-Nb和Numblike-Nbl，其在指定和维持神经元分化中发挥部分冗余功能。Nb和Nbl在小鼠和人类的大多数组织中表达，包括胚胎和成人造血组织，表明这些蛋白质在造血中可能的作用。我们采用斑马鱼来研究Numb和Numblike在造血过程中可能的功能作用，因为该系统即使在具有严重缺陷的胚胎中也可以进行详细的分析，这些缺陷在其他生物体中是致命的。在这里，我们描述了nb/nbl敲低导致斑马鱼胚胎红细胞严重减少或缺失。有趣的是，nb/nbl基因敲低的胚胎中红细胞转录因子gata 1表达严重下调。这导致成红细胞不能成熟并经历细胞凋亡。我们的研究结果表明，Notch活性增加，在胚胎注射nb/nbl吗啉，我们表明，抑制Notch激活可以部分挽救造血表型。我们的研究结果提供了第一个在体内的证据，参与Numb和Numblike在斑马鱼红系分化过程中的原始造血。此外，我们发现，至少部分地，nb/nbl morphant表型是由于造血区内增强的Notch激活，这反过来又导致原始红细胞分化缺陷。
Notch signaling is an evolutionarily conserved regulatory circuitry implicated in cell fate determination in various developmental processes including hematopoietic stem cell self-renewal and differentiation of blood lineages. Known endogenous inhibitors of Notch activity are Numb-Nb and Numblike-Nbl, which play partially redundant functions in specifying and maintaining neuronal differentiation. Nb and Nbl are expressed in most tissues including embryonic and adult hematopoietic tissues in mice and humans, suggesting possible roles for these proteins in hematopoiesis. We employed zebrafish to investigate the possible functional role of Numb and Numblike during hematopoiesis, as this system allows a detailed analysis even in embryos with severe defects that would be lethal in other organisms. Here we describe that nb/nbl knockdown results in severe reduction or absence of embryonic erythrocytes in zebrafish. Interestingly, nb/nbl knocked-down embryos present severe downregulation of the erythroid transcription factor gata1. This results in erythroblasts which fail to mature and undergo apoptosis. Our results indicate that Notch activity is increased in embryos injected with nb/nbl morpholino, and we show that inhibition of Notch activation can partially rescue the hematopoietic phenotype. Our results provide the first in vivo evidence of an involvement of Numb and Numblike in zebrafish erythroid differentiation during primitive hematopoiesis. Furthermore, we found that, at least in part, the nb/nbl morphant phenotype is due to enhanced Notch activation within hematopoietic districts, which in turn results in primitive erythroid differentiation defects.
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16.2
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