2016 Group Project 2: Difference between revisions
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===Animal models=== | ===Animal models=== | ||
'''''Drosophila''''' | |||
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos. <ref name=PMID21447553><pubmed>21447553</pubmed></ref> | |||
===Abnormalities in Notch signalling=== | ===Abnormalities in Notch signalling=== |
Revision as of 09:19, 9 September 2016
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
TBC
Central Nervous System
Early Neural Differentiation
Notch plays a major role in promoting neural commitment of cells. Lowell and colleagues (2011) used genetic manipulation to discover that the phenotype of stem cells is not affected by constitutively activated Notch in mouse embryonic stem cells (mESCs), however, interfering with Notch signalling -for example by pharmacological means- did impede neural fate determination. This role required Notch signalling via fibroblast growth factor (FGF) receptors. Furthermore, the conservation of the Notch signalling pathway within pluripotent stem cells is implied due to the existence of Notch ligands in stromal cells in human embryonic stem cells (hESCs) that induce neural differentiation. [5]
Das and colleagues (2010) manipulated Notch protein levels during specific stages of neural differentiation and found that if Notch signalling pathways were activated during day 3 of neural development for 6 hours, cell proliferation was dramatically enhanced. This was attributed to the induction by Notch of cyclin D1 expression. Without Notch signalling during neural development, there was reduced cyclin D1 levels. Manipulation of mESCs to express a dominant negative form of cyclin D1 resulted in abrogation of cell proliferation stimulated by Notch. Overall these results imply a temporally-specific role for Notch in CNS development, and that it requires cyclin D1 as a signalling molecule. [6]
Other Systems
Animal models
Drosophila
Research has shown that Notch is crucial for the formation of longitudinal connections in the Drosophila CNS. Kuzina, Song, and Giniger (2011) created temperature-sensitive mutations of Notch genes that prevented the development of mature longitudinal axon tracts. They also found that the Notch phenotype appears at the earliest stages of the development of longitudinal connections in the CNS by observing early stage 13 embryos. [7]
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.[8]
Recent and Current Research
References
- ↑ 1.0 1.1 Moore, K.L., Persaud, T.V.N. & Torchia, M.G. (2015). The developing human: clinically oriented embryology (10th ed.). Philadelphia: Saunders.
- ↑ 2.0 2.1 <pubmed>10075488</pubmed>
- ↑ <pubmed>10934030</pubmed>
- ↑ <pubmed>19917614</pubmed>
- ↑ <pubmed>16594731</pubmed>
- ↑ <pubmed>20887720</pubmed>
- ↑ <pubmed>21447553</pubmed>
- ↑ <pubmed>16773578</pubmed>