Transcriptional Regulation of Neural Crest-Derived Pharyngeal Arch Artery Development
Ivey, Kathryn Nicole
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The heart is the first organ to form and is required for growth and development of mammalian embryos. As the heart matures, formation of the outflow tract is vital to establish appropriate connections with the vasculature. This process requires contribution from specialized neural crest cells, which originate in the neural folds and migrate to give rise to specific segments of the great vessels as well as particular facial structures. Many syndromic birth defects in humans affecting the heart and face arise as a result of inappropriate development of neural crest cells and can be modeled in animals through ablation of premigratory neural crest cells or targeted deletion of genes required for their proliferation, migration or survival. However, the transcription factors and signaling molecules that specify unique subsets of neural crest cells are still being detailed. This thesis represents efforts to understand those particulars. Endothelin-1 (Et-1), a small signaling peptide, is important for development of neural crest-derived structures and targeted deletion of the gene encoding Et-1 or its receptor, Endothelin-A (EtA), results in craniofacial and outflow tract anomalies along with downregulation of particular neural crest-derived pharyngeal arch mesenchyme markers. Mice deficient for both Gaq and Ga 11 are phenotypically similar to EtA or Et-1-null mice. My analysis of expression patterns of Et-1 dependent and independent transcription factors in Gaq /G a11-deficient embryos revealed that expression of genes encoding Et-1 dependent transcription factors was specifically downregulated in the pharyngeal arches of Gaq /G a11-deficient mice indicating that Gaq and Ga11 proteins serve as intracellular mediators of Et-1 signaling in the pharyngeal arch mesenchyme. Et-1 is also important for development of the neural crest-derived fetal vessel, the ductus arteriosus, which bridges the pulmonary and systemic circulations during gestation and must close at birth for extrauterine survival. The ductus arteriosus is composed of highly differentiated, contractile smooth muscle. I found that Et-1 is expressed specifically in the smooth muscle of the ductus arteriosus during development along with Hif2a and Ap2ᠡnd that, through epistatic relationships and negative feedback regulation, these three factors cooperatively regulate development of the specialized, neural crest-derived smooth muscle of this vessel.