We have studied the Notch family of transmembrane receptors, which play a crucial role in cell fate determination. The Notch signalling pathway represents a conserved mechanism to mediate signalling between adjacent, equivalent cells and to direct them to adopt different cell fates. This process, called lateral inhibition, is involved in many processes during development e.g. bristle development in Drosophila and retina and pancreas development in vertebrates. The current view is that the Notch receptor is cleaved intracellularly upon activation by Delta or Serrate ligands on neighbouring cells. The intracellular Notch domain then translocates to the nucleus, binds to the DNA- binding factor Suppressor of Hairless (CSL in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. Several studies have demonstrated that the intracellular domain alone functions as a constitutively-active receptor. There are four known mammalian Notch receptors with overlapping patterns of expression. The role of the different receptors is poorly understood, but mutations in the receptors result in distinct genetic disorders like CADASIL and a variety of tumours CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical. Infarcts and Leukoencephalopathy) is an inherited form of stroke and dementia. The histopathological hallmarks are degeneration of vascular smooth muscle cells (VSMCs) and accumulation of granular osmiophilic material (GOM)between the degenerating VSMCs. CADASIL is caused by missense mutations in the human Notch3 gene. The mutations always affect cysteine residues located in the extracellular domain of the Notch3 receptor. There is currently no biochemical data available on the mechanism by which the mutated Notch3 receptor causes CADASIL. The aim of this study has been to understand the extent of functional diversity in the Notch receptor family. More specifically, we have investigated the molecular differences between the Notch1 and Notch3 receptors in terms of ...