Yang Chai. TGF-β Signaling and Craniofacial Morphogenesis

Cleft palate represents one of the most common congenital birth defects in the human population. Despite recent advancements in medical intervention, babies born with cleft palate often suffer multiple handicaps that significantly compromise the quality of their lives. The causes of cleft palate are numerous, including multiple genetic and environmental factors (Chai and Maxson, 2006; Dixon et al., 2011). Recent studies have identified a large number of signaling pathways that regulate hard palate development. However, the regulatory mechanisms for development of the soft palate are largely unknown. The soft palate in humans consists of five muscles that are functionally highly active in our daily lives as they form a critical component of our oropharyngeal complex. Cleft of the soft palate leads to misorientation of these muscles, causing oropharyngeal deficiency and adversely affecting speech, swallowing, breathing and hearing. Our preliminary studies have shown that TGF-β signaling is specifically required in cranial neural crest-derived cells (CNCCs) for regulating tissue-tissue interactions to control soft palate development. Furthermore, we have uncovered important TGF-β downstream target genes, such as Dlx5 and Runx2, which may play crucial roles in regulating soft palate development. Our preliminary data show that Runx2 is specifically required for regulating CNCC and myogenic progenitor interaction during soft palate development. Loss of Runx2 in CNCCs leads to cleft of the soft palate. Based on this foundation, we will test the hypothesis that TGF-β regulates the expression of key transcription factors, such as Dlx5 and Runx2, which function to mediate CNC and myogenic cell interaction to control the patterning and development of muscles in the soft palate.