All ETDs from UAB

Advisory Committee Chair

Jianbo Wang

Advisory Committee Members

Chenbei Chang

Stuart Frank

Kai Jiao

Michael Miller

Rosa Serra

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Outflow Tract (OFT) malformations underlie a majority of congenital heart defects (CHD) in humans and are a leading cause of childhood mortality. The OFT, which gives rise to the aorta and pulmonary artery of the heart, relies on the contribution of the Second Heart Field (SHF) progenitors in the pharyngeal and the splanchnic mesoderm, outside of the initial heart. OFT morphogenesis requires highly regulated SHF development involving the proliferation, differentiation and deployment of the SHF progenitors to the heart. Extensive studies elegantly demonstrate how transcriptional networks integrating signaling input from multiple pathways finely balance the proliferation and differentiation of SHF progenitors. However, the mechanisms involved in the deployment of SHF progenitors to the OFT have remained largely unknown. Here, in chapter 2, we first demonstrate that Dvl2-mediated Planar Cell Polarity (PCP) signaling is specifically required in the SHF lineage during OFT morphogenesis. Loss of PCP genes Vangl2 and Dvl1/2 and the non-canonical Wnt, Wnt5a result in severe defects in OFT elongation and looping, characteristic of comprised SHF contribution. Further, in chapter 3, our extensive genetic studies in the mouse and experimental manipulations in the chick directly demonstrate that Wnt5a is involved in the deployment of SHF progenitors from the splanchnic mesoderm to the OFT. These studies have allowed us to put forth a novel mechanism to understand how SHF progenitors may be uni-directionally and cohesively deployed in a PCP-dependent fashion to elongate the OFT and how a perturbation in Wnt5a signaling can lead to inefficient SHF deployment and abnormal OFT morphogenesis. Finally, as described in chapter 4, by performing detailed lineage analysis of the other non-canonical Wnt, Wnt11 with an inducible Wnt11-CreER BAC transgene, we have generated a high resolution expression and fate map of Wnt11 expressing cells during early development, which indicates its dynamic contribution during endoderm development, vasculogenesis and cardiac development. Together, these results have significantly enriched our understanding of PCP signaling during SHF development and OFT morphogenesis, which is essential towards designing diagnostic and therapeutic approaches toward the treatment of congenital OFT malformations.

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