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Abstract for the Seminar on June 9, 2010 at NIDCR: Developmental Biology and Prevention and Treatment of Craniofacial Malformations

Dr. Yang Chai
George and MaryLou Boone Professor
Center for Craniofacial Molecular Biology, School of Dentistry
University of Southern California, Los Angeles, CA 90033

Transforming growth factor-beta (TGF-β) signaling regulates an array of cellular events during  development and disease. Mutations in TGF-β receptors type I or II (TGFBR1 or TGFBR2) cause Loeys-Dietz syndrome in humans, which includes craniofacial malformations, such as cleft palate, calvaria and mandible defects.  Previous studies suggest that excessive TGF-β activity may be involved in the pathogenesis of some of the developmental defects in patients with TGF-β receptor mutations, however, the molecular and cellular mechanisms of these defects are unknown.  Our recent study shows that loss of Tgfbr2 in cranial neural crest (CNC) cells results in elevated Tgf-β2 in the palate.  Tgf-β2 then binds to Tgf-β receptors III and I. This unique TGF-β receptor complex associates with adaptor protein to activate a non-canonical Tgf-β signaling cascade in which p38 MAPK is activated to regulate downstream target genes during palatogenesis.  In parallel, this non-canonical TGF-β signaling is also widely used in cancer cells, therefore investigation of canonical and non-canonical TGF-β signaling holds great promise for a better understanding of the molecular regulatory mechanism of development and disease. Furthermore, our study shows that a reduction in the dosage of Tgf-β2 completely rescues the cell proliferation defect and cleft palate in Tgfbr2fl/fl;Wnt1-Cre mice.  These findings strongly suggest that the complex of Tgf-β ligand and receptor specifies the downstream signaling cascade in regulating embryogenesis. Thus, the targeted modulation of Tgf-β signaling may provide an alternative, non-surgical approach for preventing and treating congenital malformations.  This research is supported by NIDCR, NIH (R01 DE012711, U01 DE020065).

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This page last updated: February 26, 2014