The intracellular domains of Notch1 and 2 are functionally equivalent during development and carcinogenesis

Abstract

Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they do contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences we examined in detail mice in which N1ICD and N2ICD were swapped. Our data point to the conclusion that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half life of NICD/RBPjk/MAML/DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlies much of the differences between Notch1 and Notch2 in all the contexts we examined including T cell development, skin differentiation and carcinogenesis, the inner ear, the lung, and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue specific γ-secretase complexes following the ICD swap. Reinterpretation of clinical finding based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals.