The ligand-activated Notch receptor undergoes proteolytic cleavages, which release an intracellular fragment that activates target genes. Notch signalling regulates many cell fate decisions, but determining where and when it is activated has proven problematic. Now, on , Raphael Kopan and colleagues reveal a novel genetic approach in mice to locate Notch activation during development. Using an N1IP-CRE allele, in which the Notch1 intracellular fragment is replaced by Cre, they have mapped Notch activity via β-galactosidase expression. This approach is particularly novel as this transgene marks descendents of a progenitor cell. Using this technique, they identify novel roles for Notch1 signalling in the heart,vasculature, retina and stem cell compartments of self-renewing epithelia. Interestingly, high levels of Notch1 activation do not always correlate with it having an essential role, as is revealed for intestinal stem cells. Together, these findings provide new insights into Notch activation and subsequent cell fate choice. Similar studies on the other Notch receptors in the mouse should provide further new information.
