2016 Group Project 2
2016 Student Projects | ||||
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Signalling: 1 Wnt | 2 Notch | 3 FGF Receptor | 4 Hedgehog | 5 T-box | 6 TGF-Beta | ||||
2016 Group Project Topic - Signaling in Development
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Notch signalling pathway
Introduction
The Notch signalling pathway is critical for cell differentiation, proliferation, and apoptosis. It is involved in embryonic organ development through the regulation of cell-cell signalling; specifically lateral inhibition, formation of boundaries, and cell lineage assignation.[1][2]
History
Overview of Molecular Mechanisms
Four NOTCH proteins are involved in the canonical pathway. NOTCH1 to NOTCH4 are single transmembrane receptors and can interact with a variety of ligands, including NOTCH ligands (e.g. Delta ligands) and Serrate ligands (e.g. Jagged 1 [JAG1] and Jagged 2 [JAG2]). The binding between the Notch receptor and the ligand on adjacent cell induces the release of the Notch intracellular domain (NICD) via a sequence of proteolytic reactions.[1] Cell-cell interaction is therefore critical in the process of triggering Notch signalling. The NICD enters the nucleus and interacts with the Suppressor of Hairless DNA-binding protein (Su(H)) to promote transcription of Notch target genes.[2]
Roles in development
Cardiovascular
Cardiomyocyte Specification and Differentiation
It has been shown that Notch suppresses cardiomyocyte cell fate specification during early cardiogenesis. This has been demonstrated through studies such as that carried out by Rones and colleagues (2000), which used activation and inhibition of Notch signaling in Xenopus. [3] Despite the understanding that Notch signalling is crucial to embryonic myogenesis, the exact molecular mechanism remains elusive. Research by Buas and colleagues (2010) has explored such mechanisms by studying the Notch target, Hey1, which is known to suppress myogenic differentiation. They concluded that this inhibitory function of Hey1 is primarily mediated through binding near to myogenin and Mef2C promoters, which leads to cessation of target gene expression. [4]
Development of the Atrioventricular Canal
Central Nervous System
Other Systems
Animal models
Abnormalities in Notch signalling
Alagille syndrome
Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder that mainly affects the liver, heart, and kidney. In 94% of clinically diagnosed cases, a mutation in the gene encoding the Notch ligand JAG1 has been identified as a contributing factor. In combination with this, a mutation in the NOTCH2 gene has also been implicated in the diagnosis of AGS.[5]
Recent and Current Research