Syndromes and Diseases Associated with the Notch Signalling Pathway

Abstract

Abstract The Notch signalling pathway refers to a highly conserved complex cell interaction mechanism, playing a crucial role in metazoan development, which eventually dictates cell fates through the implementation of differentiation, proliferation and apoptosis, ultimately influencing organ formation and morphogenesis by unlocking specific developmental programmes. In mammals, the regulation of neurogenesis, myogenesis, angiogenesis, haematopoiesis and epithelial–mesenchymal transition are all crucially influenced by Notch signalling and to date 10 genes, either core components of the pathway or signalling targets, are implicated in a diverse group of human Mendelian diseases/syndromes when mutated in the germline. These can be broadly grouped into those conditions dominated by axial skeletal defects – the spondylocostal dysostoses; those with predominantly vascular or cardiovascular abnormalities – Alagille syndrome, NOTCH1 ‐related congenital cardiac anomalies and CADASIL; Hajdu–Cheney syndrome, a multisystem disorder dominated by skeletal anomalies, and neurological degeneration – Alzheimer disease type 3. Notch signalling is also widely implicated in somatic genomic mutational events leading to cancer and malignancy, the best known example of which is T‐cell acute lymphoblastic leukaemia. Key Concepts: Notch signalling is a highly conserved pathway in metazoan development. The Notch gene family encodes cell surface transmembrane receptors which mediate cellular functions through direct cell–cell contact. The activation of membrane‐bound Notch results in proteolytic cleavage Notch intracellular domain (NICD), which translocates to the nucleus. The Notch intracellular domain (NICD) converts downstream targets from transcriptional repressors to transcriptional activators. Notch signalling determines cell fates in neurogenesis, myogenesis, angiogenesis, haematopoiesis and epithelial–mesenchymal transition. A key role of the Notch signalling pathway is in the developmental integrity of somitogenesis. Syndromes caused by germline mutations in Notch pathway genes include spondylocostal dysostosis, Alagille and Hajdu–Cheney. Syndromes with predominantly (cardio)vascular effects due to mutations in Notch pathway genes include congenital heart disease and CADASIL. A form of familial presenile dementia (Alzheimer disease type 3) is due to mutated PSEN1 , a Notch pathway gene. Somatic mutations in certain Notch pathway genes are increasingly being shown to contribute to various cancerous conditions.