Congenital cardiovascular malformations (CCVM) are the most common human birth defects, occurring in up to 1% of newborn infants. Many cell populations are required for correct cardiovascular development, including the neural crest cells (NCC). NCCs migrate from the dorsal neural tube into the pharyngeal arches and contribute to the asymmetric remodelling of the pharyngeal arch arteries (PAA). A subset of NCCs continue to migrate into the outflow tract (OFT) of the heart, and aid in the septation of the OFT into the aorta and pulmonary trunk. Tcfap2a, which encodes the murine transcription factor AP-2α, is highly expressed within NCCs and the pharyngeal surface ectoderm (PSE), and mutations in this gene causes CCVM affecting the OFT, PAAs and the formation of the interventricular septum. This thesis investigates the tissue-specific requirements of Tcfap2a in cardiovascular development and the mechanisms of PAA malformation. Conditional deletion of Tcfap2a from NCCs resulted in a limited prevalence of CCVM, which was not increased by altering the genetic background or simultaneous deletion from the PSE. However, Tcfap2a expression within both the NCCs and PSE is required in craniofacial and thymus development. Immunohistochemical analysis in Tcfap2a-null embryos suggests that Tcfap2a is required in the formation of the PAAs, in addition to a possible role in their remodelling. Quantitative PCR analysis was used to investigate potential transcriptional targets of AP-2α within the pharyngeal arch region and we propose that Dlx5 is regulated by AP-2α in a pathway independent of endothelin signalling. A study investigating the potential interaction between these genes is presented here. This thesis presents further insights into the genetic networks regulating the formation of the PAAs, OFT and interventricular septum of the heart. We also highlight issues associated with the use of transgenic mouse models and the effect of genetic background in the study of cardiovascular development.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:627707 |
| Date | January 2014 |
| Creators | Johnson, Amy-Leigh |
| Publisher | University of Newcastle upon Tyne |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10443/2406 |
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