Abstract
The mandible is an important structure involved in the essential functions of breathing and mastication. Many human syndromes with craniofacial anomalies include defects in mandible formation. To investigate the role of Transforming growth factor β (TGF-β ) in regulating the fate of cranial neural crest cells (CNC) during mandibular, we generated the mutant mice with tissue-specific Tgfbr2 gene ablation using Cre/loxP recombination system exclusively in the cranial neural crest lineage (Tgfbr2fl/fl ; Wnt1-Cre : Tgfbr2 CKO). Tgfbr2 CKO mice show mandible defects including abnormal shape of Meckel's cartilage, small mandibular bone and perturbed chondrogenesis in the proximal region of the mandible. TGF-β signaling stimulates the proliferation activity of chondrocyte in Meckel's cartilage through Ctgf and of osteoblast in mandibular through Msx1 expression. Specifically, the appearance of chondrocytes in Tgfbr2 CKO mice is delayed and they are smaller in size in the condylar process and completely missing in the angular process. TGF-β signaling controls Sox9 expression in the proximal region, because Sox9 expression is delayed in condylar processes and missing in angular process in Tgfbr2 CKO mice. Moreover, cartilage formation is replaced by bone the results of accelerated osteoblast differentiation by elevated Runx2 and Dlx5 expression in osteo-chondroprogenitor cells. Additionally, deletion of Dlx5 in Tgfbr2 CKO mice resulted in the rescue of cartilage formation in the angular processes. Collectively, our data suggest that there are differential signal cascades in response to TGF-β to control chondrogenesis and osteogenesis during mandibular development.
