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Title: Role of neuropilins in zebrafish heart regeneration
Author: Lowe, V. J.
ISNI:       0000 0004 8499 4830
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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BACKGROUND: Unlike adult mammals, zebrafish can regenerate their heart. Several mechanisms are essential to achieve regeneration; these include: • the de-differentiation and proliferation of cardiomyocytes contributing to new myocardium, • angiogenesis to provide a blood supply to the injured area • epicardial activation, leading to the establishment of a scaffold for the proliferating cardiomyocytes, vessel supporting mural cells and cytokine secretion. Platelet-derived growth factor (Pdgf), Vascular endothelial growth factor (Vegf), Transforming Growth Factor beta (Tgfβ) and Fibroblast growth factor (Fgf) signalling play critical roles in the zebrafish heart regeneration. Neuropilins (NRPs) are cell surface co-receptors that have been implicated in VEGF, PDGF, FGF, TGFβ signalling. AIMS: I hypothesised that neuropilins are required for the regenerative response, and investigated the role of neuropilins in zebrafish heart regeneration following cryoinjury. RESULTS: Zebrafish have four neuropilins isoforms, nrp 1a, 1b, 2a and 2b. I found that all isoforms were upregulated in the ventricle following cardiac cryoinjury. Neuropilins were strongly expressed, at both the mRNA and protein level, by the activated epicardium and endocardium and at the injured/healthy myocardium border. Neuropilin upregulation coincides with leucocyte infiltration to the injured area, epicardial activation and initiation of neovascularisation, implicating a role of nrps in these processes. A nrp1a mutant, encoding a truncated, non-functional protein, showed a significant delay in heart regeneration in comparison to wild type fish. Furthermore, epicardial cells from nrp1a mutant zebrafish heart explants displayed an impaired response to activation by cryoinjury. CONCLUSIONS: Nrp1 plays a key role in zebrafish heart regeneration, mediated through epicardial activation and migration and likely contributes to further physiological processes in other cardiac cell-types. This is the first report of an injury-induced epicardial activation phenotype caused by the disruption of a single allele in zebrafish.
Supervisor: Zachary, I. ; Pellet-Many, C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available