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Title: Studies on the functions of Delta proteins in the zebrafish
Author: Leslie, Jonathan Dale
ISNI:       0000 0004 2671 6963
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2007
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The Notch cell-cell signalling pathway plays a key role both in development and in adult life, controlling cell fate decisions in a wide variety of animal tissues. At its core lie the Notch receptors and their ligands, the proteins of the Delta and Jagged/Serrate family. Both ligand and receptor are transmembrane proteins that interact via their extracellular domains, yet the intracellular domains of the Notch ligands are also important for the activation of Notch receptors on neighbouring cells. In all vertebrates we find a conserved subset of Deltas ending in the C-terminal motif ATEV*, a potential PDZ-binding sequence. This motif mediates the interaction between Delta and the members of the MAGI family of scaffolding proteins. Surprisingly, blocking this interaction has no effect on Delta-mediated processes, indicating that it is not essential for normal Delta function. However, in embryos in which the interaction between Magi and DeltaD is blocked, we find that primary motor neurons are misplaced, a phenotype not seen in the DeltaD loss of function mutant after eight. These data suggest that MAGI proteins may somehow function to restrict Delta function. Recent updates to the zebrafish genome database have revealed a novel ATEV-Delta that is orthologous to mammalian Delta-like 4 (D114), a Notch ligand essential for normal vascular development. Zebrafish dll4, like dll4 in the mouse, is expressed in arterial endothelial cells. Embryos lacking D114 initially develop normally, but at later stages exhibit an overproduction of arterial endothelial cells and excessive angiogenic sprouting. A similar phenotype is seen in embryos lacking the receptor Notch lb and in embryos in which all Notch signalling is blocked with the gamma-secretase inhibitor DAPT. Over-activation of the Notch pathway produces an opposite effect. The excessive angiogenesis observed in embryos lacking D114 is blocked by inhibition of the vascular endothelial growth factor (VEGF) signalling pathway. Thus, D114-Notch signalling acts as an angiogenic "off switch, making endothelial cells deaf to VEGF.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available