Wnt11-Signaling Regulates Cardiac and Neural Crest Development

by Garriock, Robert John.

This dissertation is composed of five major chapters. The first is a review of the literature discussing the secreted growth factor Wnt11 with particular interest in the Wnt11dependent signaling cascades that regulate cell movements, followed by three chapters of research findings, and a final concluding chapter. Wnts are encoded by a family of 19 genes that play roles in development and disease. Homologs of Wnt11 are important regulators of cell movements in gastrulating embryos. In addition to gastrulation, Wnt11 genes show expression in other embryonic tissue including neural crest cells, the heart and the somite. Following the literature review, the first three chapters describe research that studies the roles of Wnt11-signaling during the development of the heart and neural crest. The first one demonstrates that Wnt11-signaling is required for heart morphogenesis. This work also refutes a proposed role for Wnt11 as a heart inducer. Next, the role of Wnt11 homologs is studied in the regulation of cranial and trunk neural crest cell migration. During neural crest development two Wnt genes are redundantly required to regulate cell migration Wnt11 and Wnt11-related (Wnt11-R). Trunk neural crest migration requires Wnt11-R for migration into the dorsal fin. Alternatively, cranial neural crest development predominantly requires Wnt11 while more severe migratory defects are observed when Wnt11 and Wnt11-R are co-inhibited. A final chapter discusses the overall conclusions about the general role that Wnt11 genes play during embryonic development. 11 1. INTRODUCTION 1.1.What are cell movements? Cell movements underlie a broad range of morphogenetic events during embryonic development. Essentially, through differential cell adhesion and dynamic modulation of the actin cytoskeleton, individual cells are able to change shape or move across a substrate (Fig. 1.1). Alternatively, similar types of cell adhesion and de-adhesion with other cells combined with cell shape changes can cause morphogenetic changes within a group of cells. In this case, an amorphous group of cells can rearrange themselves in such a way that a group of cells form a structure of greater complexity (Fig. 1.1). These types of cell movements underlie embryonic development where a large fertilized egg cleaves into many small individual cells and finally undergo complex morphological changes to form the basic embryonic body plan with distinct cell layers and a primitive gut cavity (Wallingford et al., 2002c). 1.2.Discovery of the Wg/Wnt-signaling pathway The ability of embryonic cells to undergo morphogenetic changes requires cell to cell communication. Cell communication can occur at a variety of distances through chemical messengers or extracellular proteins. One group of extracellular proteins that participate in cell signaling is the Wnt family of secreted signaling ligands. In humans, the Wnt family is encoded by 19 distinct genes encoded throughout the genome. The 12