Tissue‐specific requirement for TGF‐β signaling during craniofacial development

Abstract

Members of the transforming growth factor‐β (TGF‐β) superfamily mediate a wide range of biological activities, including cell proliferation, differentiation, extracellular matrix formation, and induction of homeobox genes, suggesting that TGF‐β signaling is important in pattern formation and organogenesis. During craniofacial development, TGF‐β is expressed in the craniofacial epithelium and the cranial neural crest (CNC) derived mesenchyme, suggesting tissue‐specific functions in regulating craniofacial development. To investigate the tissue‐specific requirement of TGF‐β signaling, we generated animal models with epithelim or CNC‐derived mesenchyme specific inactivation of Tgfbr2 gene and investigated the molecular mechanism of TGF‐β signaling in regulating the fate of craniofacial epithelial or the CNC mesenchyme cells, respectively. Using mice with conditional inactivation of Tgfbr2 in the epithelium, we show that TGF‐β signaling is specifically required for regulating palate fusion and skin development. At the cellular level, TGF‐β signaling is critical for mediating apoptosis of MEE cells during palatal fusion. On the other hand, conditional Tgfbr2 gene ablation in the CNC resulted in complete cleft secondary palate, calvaria agenesis, and other skull defects with complete phenotype penetrance. Significantly, disruption of the TGF‐β signaling does not adversely affect CNC migration. Cleft palate in Tgfbr2 mutant mice results from a cell proliferation defect within the CNC‐derived palatal mesenchyme. The midline epithelium of the mutant palatal shelf remains functionally competent to mediate palatal fusion once the palatal shelves are placed in close contact in vitro. Our data suggests that TGF‐β IIR plays a critical, cell autonomous role in regulating the fate of MEE and CNC cells during palatogenesis. To explore the molecular mechanism of TGF‐β signaling in regulating craniofacial development, we analyzed downstream target genes affected by altered TGF‐β signaling in either the epithelium or the CNC‐derived mesenchyme. Comprehensive analysis reveals specific TGF‐β signaling network in regulating craniofacial development. Collectively, our study demonstrates that TGF‐β signaling plays an essential role in cell fate determination of the craniofacial epithelium and the CNC‐derived mesenchyme and provides a model for the study of abnormal craniofacial development.