The NOTCH gene in Drosophila codes for a membrane bound receptor, which interacts with certain ligands and transduces signals that affect key processes in neural development. NOTCH3 is the third discovered human homologue of this gene. Similarly, homologues of the Drosphila NOTCH ligand have also been observed in humans, such as Jagged1, Jagged2, and Delta1. However, the exact nature of the interaction between the human NOTCH protein and these ligands has not been understood. By homology modeling and similarity studies, it seems that the NOTCH protein is a membrane bound receptor that is activated by the binding of the above-mentioned ligands. This activation causes the cleavage of the receptor to release a peptide fragment containing the intracellular domain fragment. This leads to the formation of a transcriptional activator complex involving RBP-J kappa, which further activates genes involved in the cell cycle, mainly in the differentiation, proliferation, and apoptotic mechanisms of the cell.
Autosomal dominant mutations in the NOTCH3 gene have been shown to be the cause of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a disorder characterized by recurrent transient ischemic attacks and vascular dementia.