Regulation of Notch Signaling Pathway and Its Relation to Diseases

Dear Colleagues,

The activity of Notch, a membrane signalling receptor, mediates numerous cell-fate decisions across many tissues during development, in adult tissue homeostasis, and in stem-cell regulation. Unlike many signals, the Notch core activation mechanism does not depend on signal amplification, but instead involves proteolytic cleavages that release its intracellular domain, allowing it to relocate to the nucleus, where it acts as part of a transcription factor complex to regulate gene transcription. Despite the simplicity of this mechanism, Notch signalling amplitude, duration, and spatial patterning are tuned by a multiplicity of regulatory interactions and covalent modifications affecting both intracellular and extracellular domain that provide appropriate control of activity in different patterning contexts, such as lateral inhibition, boundary formation, and binary cell-fate decisions. In Drosophila, the multiplicity of mechanisms of Notch regulation across different tissues is revealed by mutations that are differently located in its structure which result in different gain- or loss-of-function phenotypes affecting different tissues. In humans too, loss- or gain-of-function mutations in each of the four human Notch genes, or its ligands, have been linked to different phenotypes affecting different tissues with varying degrees of pathological severity. These include congenital heart disease, vascular dementia, limb malformations, craniofacial developmental phenotypes, skeletal disorders, and defects in liver, kidney, and other organs. Notch dysregulation, either through the mutation of Notch and its regulators or by altered expression, has also been linked with numerous cancers. In cancer, as with its developmental roles, Notch shows context dependency by acting either as an oncogene or tumour suppressor in different tissues. This Special Issue aims to shed light on the links between Notch and disease and the different regulatory mechanisms liked to pathological outcomes. Areas of interest include genetic disorders and their mechanisms, Notch in cancer, structure–function studies of Notch mutations, contributions from genetic model organisms, mechanisms of Notch regulation and dysregulation, and the application of mathematical modelling to the study of Notch regulatory networks.

We look forward to receiving and reading your contributions.

Dr. Martin Baron
Guest Editor

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