Modes of Notch signalling in development and disease

Many different animal developmental and homeostatic processes rely on signalling via the highly conserved Notch pathway. Often Notch signalling has iterative roles during cell specification and differentiation, controlling not only the state of progenitor cells but also the fate and function of their progeny. Its roles continue throughout the lifespan of the organism, regulating normal tissue maintenance, as well as operating in response to damage. Consistent with such fundamental roles, the pathway has been associated with numerous diseases, including cancers. Understanding how Notch signalling is orchestrated to bring about different outcomes is challenging, given that it has many diverse functions. Classic models proposed that stochastic differences in cell states were important to polarise signalling during cell fate decisions. Subsequently, the importance of oscillatory Notch signalling was uncovered, and it became clear that it operates in different modalities depending on the regulatory inputs. With the advent of ever-more-sensitive live-imaging and quantitative approaches, it is becoming evident that differences in the dynamics, levels and architectures of Notch signalling are critical in shaping and maintaining tissues. This Review focuses on the cellular and molecular mechanisms involved in conferring different modalities on Notch pathway operations and how these enable different types of functional outcomes from pathway activation. We also discuss their dysregulation in cancer.