Fbw7 Repression by Hes5 Creates a Feedback Loop That Modulates Notch-Mediated Intestinal and Neural Stem Cell Fate Decisions

Abstract

Author SummaryThe Notch signalling pathway is a highly conserved system that controls cell differentiation decisions in a wide range of animal species and cell types, and at different steps during cell lineage progression. An important function of the Notch pathway is in lateral inhibition—an interaction between equal adjacent cells that drives them towards different final states. The basic principle of lateral inhibition is that activation of the Notch cell surface receptor represses production of the Notch ligand (also borne on the cell surface). Consequently, cells expressing less Notch produce more Notch ligand that can activate the Notch pathway in neighboring cells and thereby amplify the differences between these cells. However, the additional regulatory circuits required to fine-tune this delicate process have so far remained elusive. Here we describe the identification of a novel intracellular positive feedback loop that connects Fbw7 (the ubiquitin ligase responsible for targeting Notch for degradation) and Notch itself. We show that Fbw7 reduces the stability of Notch intracellular domain (NICD) protein, as previously established, but also that the fbw7 gene is itself transcriptionally downregulated by the Notch effector Hes5. Thus we conclude that increased Notch activity causes NICD stabilisation. Further, we demonstrate that perturbation of this regulatory loop is responsible for the Fbw7 haploinsufficiency observed for Notch-dependent functions in intestine and brain stem cells.