Turn it down a notch

In the developing vertebrate embryo, segmentation initiates very early and in a species-specific manner through the formation of repeated segments,termed somites, that form on either side of the neural tube along the anterior to posterior axis. The periodicity of somite formation is regulated by a molecular oscillator, called the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signalling pathways have been proposed to underlie the molecular mechanism of the oscillator: Wnt, Fgf and Notch. In particular, the Notch signalling pathway has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and this signalling pathway is necessary for somite formation and clock gene oscillations. Also, the pace of the segmentation clock is exquisitely sensitive to levels/stability of the labile Notch intracellular domain (NICD). To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain by two kinases, namely cyclin-dependent kinase-8 (CDK8) and glycogen synthase kinase 3 beta (GSK-3β). NICD phosphorylation is also a fundamental step in the recognition process by SCF Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. In this review, we will provide a detailed overview of the Notch pathway, highlighting its role in somitogenesis as one example of a key role for this pathway in embryogenesis and focusing on the regulation of NICD degradation by FBXW7. We will also describe the pathophysiological relevance of the interaction between NICD and FBXW7, whose defects have been linked to leukemia and a variety of solid cancers.