@phdthesis{discovery14469,
           month = {January},
           title = {A study of Notch signalling in developmental angiogenesis},
            note = {Unpublished},
            year = {2009},
          school = {UCL (University College London)},
             url = {https://discovery.ucl.ac.uk/id/eprint/14469/},
        abstract = {Blood vessel patterning during angiogenesis is a guided process. Endothelial tip cells
located at the end of vascular sprouts are important for vessel guidance. One of the
aims of my studies is to determine how endothelial tip cell formation is regulated.
Previous studies have shown that the Notch ligand, Delta-like 4 (Dll4), is
prominently expressed in tip cells, therefore suggesting a role of Notch signalling in
its regulation. In the mouse, suppression of Notch signalling by pharmacological
inhibition of {\ensuremath{\gamma}}-secretase or genetic deletion of one Dll4 allele resulted in excessive
endothelial tip cell formation and a poorly-patterned, hyperdense vessel network.
Induction of Notch signalling by Jagged1 peptide treatment led to a decrease in tip
cell formation and a sparse vessel network. Thus, the Notch pathway negatively
regulates tip cell formation to promote a non-sprouting endothelial stalk cell.
The Notch-regulated ankyrin repeat protein, Nrarp, is a Notch target gene
that is highly expressed in stalk cells and endothelial cells located at vessel
branchpoints. Deletion of Nrarp in mouse and morpholino knockdown of nrarp-a
and nrarp-b in zebrafish resulted in decreased endothelial cell proliferation and
junctional instability, leading to ectopic vessel regression and the formation of a
sparse vessel network. In endothelial cells, loss of Nrarp function increased Notch
signalling but decreased Wnt signalling, thereby confirming its role as a negative and
positive modulator of Notch and Wnt signalling, respectively. Mice null for
Lymphoid enhancer factor 1 (Lef1) or deficient in endothelial Ctnnb1 also displayed
increased vessel regression and decreased vessel density, suggesting a role of
canonical Wnt/{\ensuremath{\beta}}-catenin signalling in maintaining vessel stability.
In conclusion, my studies show that Notch signalling regulates endothelial tip
cell formation and vessel stability to fine-tune vessel patterning. Furthermore, I
demonstrate that Nrarp provides a molecular link to Wnt signalling to regulate vessel
stability.},
          author = {Phng, L.-K.}
}