Carrieri Francesca A, Dale Jacqueline Kim
Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee Dundee, UK.
Front Cell Dev Biol. 2017 Jan 18;4:151. doi: 10.3389/fcell.2016.00151. eCollection 2016.
In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers.
在发育中的脊椎动物胚胎中,体节形成是通过沿前后轴在后侧神经管两侧形成重复的节段,即体节来启动的。体节发生的周期性由分子振荡器——体节时钟调节,该时钟驱动未分段的近轴中胚层(体节由此发育而来)中的基因循环表达。三种信号通路构成了振荡器的分子机制基础:Wnt、FGF和Notch。特别是,Notch已被证明是复杂的体节发生调节难题中的关键一环。Notch对于使相邻细胞之间的振荡同步是必需的,而且对于体节形成和时钟基因振荡也是必需的。在配体激活后,Notch受体被切割以释放活性细胞内结构域(NICD),并且在体节发生过程中,NICD自身以周期性方式产生和降解,这需要严格调控和协调的周转。最近的研究表明,体节时钟的节奏对NICD的水平/稳定性极为敏感。在本综述中,我们重点关注已知的调节NICD周转的机制,这对于该通路在所有发育背景下的活性至关重要。迄今为止,NICD稳定性的调节归因于PEST结构域的磷酸化,该结构域用于募集参与NICD周转的SCF/Sel10/FBXW7 E3泛素连接酶复合物。我们将描述NICD-FBXW7相互作用的病理生理学相关性,其缺陷与白血病和多种实体癌有关。