Notch-3

null Notch-3 stands out within the Notch receptor family for its highly restricted expression in vascular smooth muscle cells and pericytes of small arteries, where it regulates vessel maturation and arterial specification. Signaling follows the canonical scheme: Delta-like and Jagged ligand binding induces ADAM and gamma-secretase cleavage, releasing the intracellular domain that activates RBPJ-dependent transcription of HES and HEY genes. Unlike Notch-1 and Notch-2, Notch-3 is dispensable for most embryonic development but essential for postnatal vascular remodeling. Numerous cysteine-altering missense mutations clustered in its extracellular EGF-like repeats cause CADASIL, a hereditary small-vessel disease characterized by stroke and early-onset dementia.