Bmp signaling and palate development
Description
Growth factors play essential roles in embryonic development. Bone morphogenetic proteins (Bmps) constitute a subfamily of transforming growth factors (Tgfbeta) and are important for multiple developmental events, including craniofacial development. Deregulation of Bmp signaling has been implicated in formation of cleft palate, one of most common human birth defects. However, the mechanisms, how Bmp signaling regulates palate development and how its function is modulated, remain unknown. This dissertation has been designed to answer these questions Noggin is a secreted Bmp extracellular antagonist by blocking Bmp signaling through interfering ligand-receptor binding. When examining the craniofacial defects in Nog-/- mice, I found that they have cleft palate phenotype and Noggin is expressed in the developing palate restricted to the oral side palatal epithelium. In Chapter II, I use Nog-/- mice as a model to study the role of Bmp signaling in palate development. I found that Bmp signaling is ectopically activated in Nog-/- palatal epithelium, accompanied with elevated level of cell proliferation and cell death. In the posterior palate, ectopic cell death leads to abnormal palate-mandible fusion and blocks normal palate elevation, generating a cleft palate phenotype. By manipulating the Bmp signaling activity, I have managed to recapitulate this unique palate-mandible fusion. Therefore, I demonstrated that Noggin mediated silencing of Bmp signaling is required to maintain palatal epithelium integrity to ensure normal palate development During palate development, Bmps expression is restricted to the mesenchyme and it has been shown that Bmp4 functions to maintain epithelial Shh expression. Such epithelial-mesenchymal interaction is not only important for palate formation, but also prevalent in general embryonic development. It is unknown how these two growth factors interact. In chapter III, I focused on delineating the regulatory mechanism between Bmp4 and Shh in the model of secondary palate. I found that Hand2 is expressed in both palatal epithelium and mesenchyme. Hand2 hypomorphic mice exhibit cleft palate phenotype with down-regulation of Shh and its downstream targets. While in Bmp loss-of-function model, expression of Hand2 and Shh is specifically downregulated in the developing palate, demonstrating that Hand2 mediates Bmp4-Shh regulation during the epithelial-mesenchymal interaction in palate development