Abstract
Notch3 is one of four mammalian Notch proteins, which act as signalling receptors to control cell fate in many developmental and adult tissue contexts. Notch signalling continues to be important in the adult organism for tissue maintenance and renewal and mis-regulation of Notch is involved in many diseases. Genetic studies have shown that Notch3 gene knockouts are viable and have limited developmental defects, focussed mostly on defects in the arterial smooth muscle cell lineage. Additional studies have revealed overlapping roles for Notch3 with other Notch proteins, which widen the range of developmental functions. In the adult, Notch3, in collaboration with other Notch proteins, is involved in stem cell regulation in different tissues in stem cell regulation in different tissues, and it also controls the plasticity of the vascular smooth muscle phenotype involved in arterial vessel remodelling. Overexpression, gene amplification and mis-activation of Notch3 are associated with different cancers, in particular triple negative breast cancer and ovarian cancer. Mutations of Notch3 are associated with a dominantly inherited disease CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and there is further evidence linking Notch3 misregulation to hypertensive disease. Here we discuss the distinctive roles of Notch3 in development, health and disease, different views as to the underlying mechanisms of its activation and misregulation in different contexts and potential for therapeutic intervention.
Highlights
Notch is a transmembrane, developmental signalling receptor, which plays many crucial roles in developmental patterning, cell fate decisions, regulation of cell survival and proliferation [1,2,3]
Further differences are located in the intracellular domain (ICD) which is shorter for Notch3 and 4 and lacks a region thought to act as a transcriptional activator domain (TAD) (Figure 1)
Aberrant Notch signalling was first linked to human cancer through the identification of a chromosome translocation, in T-cell acute lymphoblastic leukaemia (T-ALL), that resulted in the expression of the soluble cytoplasmic domain of Notch1, which was constitutively active, linking ectopic Notch activity to cancer progression [50]
Summary
Developmental signalling receptor, which plays many crucial roles in developmental patterning, cell fate decisions, regulation of cell survival and proliferation [1,2,3]. An interesting recent study combining experimental observations and computational modelling has revealed that Jagged-1-induced Notch sBiigomnoalellciunlegs 2d0e20c,r1e0a,s4e8s5 with increased mechanical load with a switch between contractile and synt4hoefti1c7 VSMC phenotype linked to changes in thickness in the VSMC wall that encloses the endothelial cells that form the artery vessel (Figure 3) [42]. Notch3-deficient adult mice show further progressive phenotypes in brain and retinal vasculature, resulting from vascular smooth muscle cell degeneration and loss through apoptosis [40] This causes loss of vessel integrity, haemorrhage and loss of blood–brain barrier function. An interesting recent study combining experimental observations and computational modelling has revealed that Jagged-1-induced Notch signalling decreases with increased mechanical load with a switch between contractile and synthetic VSMC phenotype linked to changes in thickness in the VSMC wall that encloses the endothelial cells that form the artery vessel (Figure 3) [42]. Notch signalling activates Notch expression, which in turn promotes oesophageal squamous cell differentiation [49]
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