Notch signal strength controls cell fate in the haemogenic endothelium.
Notch signal strength controls cell fate in the haemogenic endothelium.
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DOI：
10.1038/ncomms9510
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发表时间：
2015-10-14
影响因子：
16.6
通讯作者：
Bigas A
中科院分区：
文献类型：
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作者：
Gama-Norton L;Ferrando E;Ruiz-Herguido C;Liu Z;Guiu J;Islam AB;Lee SU;Yan M;Guidos CJ;López-Bigas N;Maeda T;Espinosa L;Kopan R;Bigas A
在造血干细胞(HSC)生成之前，动脉和血源性内皮命运的获得同时发生在主动脉-性腺-中肾(AGM)区域。动脉程序依赖于DLL4和血源性内皮/HSC依赖于Jag1介导的Notch1信号。Notch1如何区分和执行这些不同的程序，以响应特定的配体，人们知之甚少。通过使用两种不同敏感性的Notch1激活陷阱小鼠模型，我们发现动脉内皮细胞和HSC起源于不同的前体，具有不同的Notch1信号强度。对AGM亚群的微阵列分析表明，Jag1配体刺激低Notch强度，抑制内皮程序，并允许HSC规范。在缺乏Jag1的情况下，内皮细胞经历DLL4诱导的高Notch活性，并选择内皮程序，从而阻止HSC的形成。配体特异性阻断抗体对DLL4信号的干扰足以抑制内皮程序，有利于指定造血系。目前尚不清楚Notch1信号如何调控胚胎主动脉内皮细胞命运的维持和内皮细胞向造血细胞的转变。在这里，作者表明，那些Notch1配体Jag1被DLL4竞争对手的细胞仍然是内皮细胞，而更高的Jag1活性会导致造血干细胞的产生。
Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta–gonad–mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage. It is unclear how Notch1 signals regulate both the maintenance of the endothelial fate and the endothelial-to-hematopoietic transition in the embryonic aorta. Here the authors show that those cells in which Notch1 ligand Jag1 is out-competed by Dll4 remain endothelial, while higher Jag1 activity leads to generation of hematopoietic stem cells.