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Title: The-role of neural crest cells in the septation of the cardiac outflow and the effects of vitamin supplementation.
Author: Bradshaw, Lucy
ISNI:       0000 0001 3476 2036
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2007
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Septation of the initially single cardiac outflow tract (OFT) into the distinct vessels of the aorta and pulmonary trunk is a crucial step in the development ofthe mature heart and is dependent upon two cell types; cardiac neural crest cells (NCe) and a contribution from the secondary heart field. Vitamin supplementation has been implicated as one of a number of environmental 'factors to influence the occurrence of congenital heart defects. Folic acid has been shown to rescue some neural tube and conotruncal heart defects whereas retinoic acid is critical for the formation of the outflow tract, but teratogenic in excess. The aim of the first part of this study was to investigate how the deficiency of NC~ in the Splotch2H mouse mutant causes OFT defects by. lineage tracing Wntl-expressing cells and how this may, in turn, affect the behaviour of SHF-derived cells. NCC's did not sufficiently colonise the caudal pharyngeal arches of Sp2H/Sp2H embryos, and as a consequence the 4th arch was completely absent. Reduced numbers of NCC were also observed in the dorsal wall of the aortic sac (aorto-pulmonary septum) and the proximal outflow cushion leading to a single, unseptated outflow vessel. This loss of NCC caused the ectopic localisation of Isletl-positive secondary heart field cells in the distal outflow tract, leading to abnormal myocardialisation and alignment defects. Thus, the outflow malformations seen in Sp2H/siH fetuses result from a combination of direct deficiency of NCC together with secondary effects on cells of SHF origin. Unravelling the relationship between these two cell types is likely to be of major importance in understanding the aetiology of malformations affecting the outflow region in humans. Secondly, the effects of supplementary exogenous vitamins on NCC were studied, to elucidate potential mechanisms for the rescue of neural-crest dependent OFT structures. Additional folic acid directly affected the NCC of Sp2H/Sp2H fetuses, exacerbating their intrinsic role to stabilise the developing pharyngeal arches, in particular the maintenance of right-sided arch structures. Retinoic acid did not alter the outflow tract defects ofsiH/sp2H fetuses, but did induce a variety of non-neural crest-dependent alignment/rotation defects in Sp2H/+ and wild-type fetuses at high doses, implicating the SHF as a potential target of Vitamin A teratogenicity. Although the exact mechanisms by which these vitamins exert their effects are still largely elusive, this study is an important step towards paving the way to primary prevention of a major group of congenital heart defects.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available