Role of BMP Antagonism in Craniofacial and Foregut Development

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An exciting finding of recent research in developmental biology is that defective development of the rostral foregut endoderm (FGE) can result in both intrinsic and extrinsic malformations of direct relevance to major human birth defects. An important group of foregut defects is tracheoesophageal fistula, where the trachea and esophagus fail to be formed correctly from the early endodermal tube. The FGE is also the source of critical signals that regulate craniofacial development; for example, defective foregut signaling can lead to severe mandibular hypoplasia (underdevelopment of the lower jaw). Despite their pragmatic importance, the mechanisms controlling these intrinsic and extrinsic aspects of foregut development remain largely unknown. The long-term objective of our work is to understand how intercellular signaling directs the development of rostral tissues in the mouse embryo. Our previous work showed that loss of the BMP antagonists Noggin and Chordin results in both tracheo-esophageal fistula and mandibular hypoplasia. These BMP antagonists are expressed in the anterior primitive streak, the source of the FGE. Later, they are expressed in the axial midline, including floorplate, notochord and dorsal FGE. Based on our current data, our central hypothesis is that ongoing axial midline BMP antagonism is an active regulator of an endodermal signaling network essential for foregut and craniofacial development. However, there is also evidence consistent with the alternative hypothesis: That in either case the relevant requirement for BMP antagonism is during and immediately after gastrulation for normal formation of the early foregut endoderm, and thus indirectly for the foregut's subsequent intrinsic and extrinsic developmental roles. Resolving these questions will provide key insight into the essential roles of BMP antagonism and the mechanisms of these birth defects in general. Accordingly, we directly test both our central and alternative hypotheses, by means of the following specific aims: 1. Determine the tissues in which BMP antagonist expression is required for formation of the trachea and esophagus; 2. Determine the spatiotemporal requirement for Noggin and Chordin in mandibular outgrowth; and 3. Determine the interactions of BMP antagonism with the foregut endodermal signaling network.