Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype
Jagged-Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype
复制标题
DOI：
10.1073/pnas.1416287112
复制
发表时间：
2015-02-03
影响因子：
11.1
通讯作者：
Ben-Jacob, Eshel
中科院分区：
文献类型：
--
作者：
Boareto, Marcelo;Jolly, Mohit Kumar;Ben-Jacob, Eshel
Notch信号通路介导胚胎发育、伤口愈合和肿瘤发生过程中的细胞命运决定。当一个细胞的配体Delta或配体Jagged与其相邻细胞的Notch受体相互作用时，该途径被激活，释放出激活许多下游靶基因的Notch胞内结构域（NICD）。NICD不对称地影响配体的产生-它抑制Delta，但激活Jagged。尽管Notch-Jagged信号传导的动力学作用仍然难以捉摸，但人们普遍认为Notch-Delta信号传导表现为细胞间的拨动开关，导致相邻细胞采用两种不同的命运-受体（高配体，低受体）和受体（低配体，高受体）。在这里，我们设计了一个特定的理论框架，将Delta和Jagged结合在Notch信号通路中，以探索Jagged在细胞命运决定中的功能作用。我们发现，NICD的不对称效应使电路表现为一个三向开关，从而产生一个额外的状态-一个混合的受体/受体（中等配体，中等受体）。这种表型允许相邻细胞发送和接收信号，从而获得相似的命运。我们还表明，由于糖基转移酶条纹的不对称效应，产生不同的结果取决于哪个配体是占主导地位的：三角洲介导的信号驱动相邻的细胞有一个相反的命运;锯齿介导的信号驱动细胞保持类似的命运，它的邻居。我们阐明锯齿状的细胞命运的决定的作用，并讨论其可能的影响，在理解肿瘤间质的串扰，这往往需要缺口锯齿通信。
Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically-it represses Delta, but activates Jagged. Although the dynamical role of Notch-Jagged signaling remains elusive, it is widely recognized that Notch-Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt-Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state-a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor-stroma cross-talk, which frequently entails Notch-Jagged communication.