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Dynamic Ligand Discrimination in the Notch Signaling Pathway.
Cell ( IF 64.5 ) Pub Date : 2018-Feb-08 , DOI: 10.1016/j.cell.2018.01.002
Nagarajan Nandagopal 1 , Leah A Santat 1 , Lauren LeBon 2 , David Sprinzak 3 , Marianne E Bronner 4 , Michael B Elowitz 5
Affiliation  

The Notch signaling pathway comprises multiple ligands that are used in distinct biological contexts. In principle, different ligands could activate distinct target programs in signal-receiving cells, but it is unclear how such ligand discrimination could occur. Here, we show that cells use dynamics to discriminate signaling by the ligands Dll1 and Dll4 through the Notch1 receptor. Quantitative single-cell imaging revealed that Dll1 activates Notch1 in discrete, frequency-modulated pulses that specifically upregulate the Notch target gene Hes1. By contrast, Dll4 activates Notch1 in a sustained, amplitude-modulated manner that predominantly upregulates Hey1 and HeyL. Ectopic expression of Dll1 or Dll4 in chick neural crest produced opposite effects on myogenic differentiation, showing that ligand discrimination can occur in vivo. Finally, analysis of chimeric ligands suggests that ligand-receptor clustering underlies dynamic encoding of ligand identity. The ability of the pathway to utilize ligands as distinct communication channels has implications for diverse Notch-dependent processes.

中文翻译:

缺口信号通路中的动态配体区分。

Notch信号传导途径包含在不同生物学环境中使用的多个配体。原则上,不同的配体可以激活信号接收细胞中的不同靶标程序,但是尚不清楚这种配体如何发生分化。在这里,我们显示细胞使用动力学来区分通过Notch1受体的配体Dll1和Dll4的信号传导。定量单细胞成像显示,Dll1在特定上调Notch目标基因Hes1的离散频率调制脉冲中激活Notch1。相比之下,Dll4以持续的幅度调制方式激活Notch1,主要上调Hey1和HeyL。Dll1或Dll4在鸡神经c中的异位表达对成肌分化产生相反的作用,表明配体识别可以在体内发生。最后,嵌合配体的分析表明,配体-受体簇聚是配体同一性动态编码的基础。该途径利用配体作为不同的通信通道的能力对多种依赖于Notch的过程具有影响。
更新日期:2018-02-01
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