| Summary: | The work presented in this thesis is an investigation into the roles of p53, Nodal/ Activin and fibroblast growth factor (FGF) signalling in early heart development in the model organism Xenopus laevis. The first step of heart development is the specification of cardiac tissue. However, the timing of cardiac specification and the signals which control it are largely unknown. The Nodal/ Activin and FGF signalling pathways have been implicated in cardiac specification but there is little evidence demonstrating a direct role for these pathways. Using soluble molecular inhibitors of the Nodal/ Activin and FGF signalling pathways at different stages of development, the effects of time-controlled inhibition on cardiac progenitor cells and differentiated cardiac tissue were observed. Nodal/ Activin signalling was found to be required for cardiac specification during a 2-3 hour time window following midblastula transition. It was shown that FGF signalling is not required prior to gastrulation for cardiac specification, but is required later for normal heart development. It was hypothesised that p53 may be involved in cardiac specification by mediating crosstalk between the Nodal/ Activin and FGF signalling pathways, in a similar manner to its previously suggested role in mesoderm induction. Using a combination of p53 antisense morpholino oligonucleotides and a dominant negative p53 protein, the effects of p53 downregulation on cardiac progenitor cells and differentiated cardiac tissue were examined. A novel role for p53 in early heart development was found. These findings contribute to an understanding of how p53, Nodal/ Activin and FGF signalling orchestrate numerous developmental events in the early embryo. This knowledge will be useful to advance our understanding of congenital heart diseases and for the development of improved directed differentiation protocols for cardiac regenerative medicine.
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