The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985 that the gene was shown to encode a transmembrane surface receptor, the core signaling component of the pathway.
The notch receptor present on the target cell surface undergoes two proteolytic cleavages after its direct interaction with the Delta/Serrate ligand expressed on the surface of the signaling cell. These proteolytic cleavages – sequentially mediated by ADAM metalloproteinases and the γ-Secretase complex – release the cytosolic part of the receptor, called the Notch intracellular domain (NICD), from the membrane into the cell. This NICD is the active signaling molecule, which then translocates to the nucleus where it directly participates in the regulation of the expression of Notch target genes.
The notch signaling is a complex signaling circuitry regulated at various levels:
Recent studies on vertebrates and invertebrates indicate that besides driving multiple aspects of metazoan development, the notch signaling pathway also controls stem cell fate and maintenance in adult tissues. However, the pathway is gene dosage-sensitive, and the appropriate level of signaling is vital for normal differentiation and tissue homeostasis. Any dysregulation in the pathway, either by direct mutations or altered signaling output, may lead to disease states. These include vascular dementia, and developmental disorders like Adams-Oliver syndrome, or Alagille syndrome.
