Institute for Research in Biomedicine (IRB Barcelona), Parc Científic de Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Curr Biol. 2010 Mar 23;20(6):554-60. doi: 10.1016/j.cub.2010.01.058. Epub 2010 Mar 11.
Notch and its ligands mediate short-range cell interactions that play a conserved role in inducing cell fate specification. Several regulatory mechanisms have been described to ensure robust polarized signaling from signal-sending to signal-receiving cells. High levels of ligand expression activate Notch in nearby cells and exert a cell-autonomous dominant-negative effect on Notch activity. This regulatory process is called cis-inhibition and helps to restrict Notch activation to signal-receiving cells. By combining genetic mosaics in the Drosophila wing primordium with cell culture assays, we present evidence here that Notch promotes the clearance of Serrate ligand from the cell surface and exerts an inhibitory effect on the activity of Serrate expressed in the same cell. These regulatory mechanisms are independent of Notch-mediated transcription and are executed by the extracellular domain of Notch. We show that this process is required to block Serrate-mediated activation of Notch in the signal-sending cell population and helps to restrict Notch activation to the signal-receiving cells. Altogether, our results, in concert with previous results on ligand-mediated Notch cis-inhibition, indicate that mutual inhibition between ligand and receptor in signal-sending cells helps to block Notch activity in these cells and to restrict receptor activation in signal-receiving cells.
Notch 及其配体介导短程细胞相互作用,在诱导细胞命运特化中发挥保守作用。已经描述了几种调节机制,以确保从信号发送细胞到信号接收细胞的极化信号的稳健传递。高浓度的配体表达在附近的细胞中激活 Notch,并对 Notch 活性产生细胞自主的显性负效应。这个调节过程称为顺式抑制,有助于将 Notch 的激活限制在信号接收细胞中。通过将果蝇翅膀原基中的遗传嵌合体与细胞培养测定相结合,我们在这里提出证据表明 Notch 促进 Serrate 配体从细胞表面清除,并对同一细胞中表达的 Serrate 活性施加抑制作用。这些调节机制独立于 Notch 介导的转录,并由 Notch 的细胞外结构域执行。我们表明,这个过程对于阻止信号发送细胞中 Serrate 介导的 Notch 激活是必需的,并有助于将 Notch 的激活限制在信号接收细胞中。总之,我们的结果与先前关于配体介导的 Notch 顺式抑制的结果一致,表明信号发送细胞中配体和受体之间的相互抑制有助于阻止这些细胞中的 Notch 活性,并限制信号接收细胞中的受体激活。