TGF-ß signaling in regulating chondrogenesis and osteogenesis during mandibular development

*1239 TGF-ß signaling in regulating chondrogenesis and osteogenesis during mandibular development*
K. OKA¹, S. OKA², T. SASAKI², Y. ITO², P. BRINGAS JR.², K. NONAKA¹, and Y. CHAI², ¹Kyushu University, Fukuoka, Japan, ²University of Southern California, Los Angeles, USA Objectives: To examine the specific cellular and molecular mechanisms by which TGF-b signaling regulates the fate of cranial neural crest (CNC) cells during mandibular development. Methods: We used the mutant mice with conditional inactivation of Tgfbr2 in the neural crest (Tgfbr2fl/fl;Wnt1-Cre). These mutant mice have severe defects in mandibular development. Results: All Tgfbr2fl/fl;Wnt1-Cre mutant mice have identical mandible defects, consisting of small mandible bones, diminished condylar and coronoid processes and absent angular processes. Furthermore, we observed an abnormal shape of Meckel's cartilage, with a curvy form and non-uniform thickness areas. We show that loss of Tgfbr2 does not affect the migration of CNC cells during Meckel's cartilage and mandibular bone development. TGF-b signaling is specifically required for cell proliferation in Meckel's cartilage and the mandibular anlagen. TGF-b signaling controls Msx1 expression to regulate mandibular osteogenesis as Msx1 mRNA expression is significantly reduced in Tgfbr2fl/fl;Wnt1-Cre mutants. Furthermore, TGF-b-mediated connective tissue growth factor (CTGF) signaling is critical for chondrocytes proliferation in Meckel's cartilage. The differentiation of chondrocytes in Meckel's cartilage is accelerated in Tgfbr2fl/fl;Wnt1-Cre mutants, with abnormal ossification (bone color like structure) in proximal part of Meckel's cartilage. Exogenous CTGF rescues the cell proliferation defect in Meckel's cartilage of Tgfbr2fl/fl;Wnt1-Cre mutants, demonstrating the biological significance of this signaling cascade in chondrogenesis during mandibular development. Conclusion: Our data suggest that there are differential signal cascades in response to TGF-b that control chondrogenesis and osteogenesis during mandibular development. This study was supported by grants from the National Institute of Dental and Craniofacial Research, NIH (DE012711, DE014078 and DE017007).
Seq #132 - Cleft Palate/Craniofacial Development 1 3:30 PM-4:45 PM, Thursday, March 22, 2007 Ernest N. Morial Convention Center Exhibit Hall I2-J
Back to the Craniofacial Biology Program Back to the IADR/AADR/CADR 85th General Session and Exhibition (March 21-24, 2007)
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