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Title: Ligand-mediated Notch receptor activation in retinal proliferation and pathologies
Author: Duckett, A. S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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The Notch family of receptors play important roles in cell fate assignation and pattern formation during development. Notch ligands, encoded by multiple Delta and Serrate/Jagged genes, have functionally significant differences in the way they interact with Notch, and the relative gene dosages of Notch and its ligands are crucial for normal development, reflected in phenotypes that correlate with copy number. Serrate and Delta have structural and functional similarities, but exhibit different expression patterns and mutant phenotypes, indicating there might be differences in the way Delta and Serrate bind to and elicit a signal from Notch. Genetic analyses have suggested the associations of Notch with its ligand in cultured cells are analogous to those in vivo. The ability of stably transfected Notch-expressing S2 cells to aggregate with Delta- or Serrate-expressing cells was examined, and unlike the binding of Delta to Notch, which is primarily dependent on the relative amounts of each protein, an additional factor influencing Notch:Serrate binding. In Drosophila, the activity of Serrate, and the way it interacts with Notch, is modulated by relative concentrations of Serrate, Notch and Wingless. Addition of Wingless to Notch- and Serrate-expressing cells promotes their aggregation, indicating Wingless facilities binding of Serrate to Notch, which would activate Notch signalling. In addition, preincubation of Notch with Wingless blocked its ability to subsequently bind Delta, indicating Wingless may change the conformation of the Notch protein. In vivo, this could profoundingly affect signalling if Wingless both blocked Delta and promoted Serrate interactions with Notch. I also present evidence that these interactions are mediated by different EGF-like repeats of Notch. Retinal progenitor cells can differentiate into any one of the neuronal or glial cell types of the mature retina and require temporal and positional information cues to adopt appropriate fates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available