Tuning of Neural Development Via Lateral Inhibition by Bi-Directional Notch-Delta Signaling

Notch-Delta signaling regulates many developmental processes, including tissue homeostasis, and maintenance of stem cells. This signaling pathway is thought to be unidirectional and is triggered by binding of Delta/Serrate/Lag2 (DSL) ligands to the Notch receptor, which leads to cleavage and activation of Notch intracellular domain (NICD). Although the cleavage of DSL ligands has also been reported, the functional significance remains poorly understood. Here, we show that reverse signaling is functional, by modulating the production of Delta like 1 intracellular domain (D1ICD). We find sustained D1ICD production abrogates cell proliferation and enhances neurogenesis, whereas inhibiting D1ICD production leads to promotion of cell proliferation and gliogenesis. D1ICD suppresses Notch signaling through up regulation of Numb, a mediator of lateral inhibition. In addition, D1ICD promotes neurogenesis through a Notch signaling independent manner by inhibiting Erk1/2 phosphorylation. Our results demonstrate that D1ICD has biological functions, and we propose Notch-Delta signaling is, in fact, bi-directional.