TGF-beta type I receptor Alk5 regulates tooth initiation and mandible patterning in a type II receptor-independent manner.
TGF-beta superfamily members signal through a heteromeric receptor complex to regulate craniofacial development. TGF-beta type II receptor appears to bind only TGF-beta, whereas TGF-beta type I receptor (ALK5) also binds to ligands in addition to TGF-beta. Our previous work has shown that conditional inactivation of Tgfbr2 in the neural crest cells of mice leads to severe craniofacial bone defects. In this study, we examine and compare the defects of TGF-beta type II receptor (Wnt1-Cre;Tgfbr2(fl/fl)) and TGF-beta type I receptor/Alk5 (Wnt1-Cre;Alk5(fl)(/fl)) conditional knockout mice. Loss of Alk5 in the neural crest tissue resulted in phenotypes not seen in the Tgfbr2 mutant, including delayed tooth initiation and development, defects in early mandible patterning and altered expression of key patterning genes including Msx1, Bmp4, Bmp2, Pax9, Alx4, Lhx6/7 and Gsc. Alk5 controls the survival of CNC cells by regulating expression of Gsc and other genes in the proximal aboral region of the developing mandible. We conclude that ALK5 regulates tooth initiation and early mandible patterning through a pathway independent of Tgfbr2. There is an intrinsic requirement for Alk5 signal in regulating the fate of CNC cells during tooth and mandible development.
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Hu
H
Zhao
Kyoko
K
Oka
Pablo
P
Bringas
Vesa
V
Kaartinen
Yang
Y
Chai
D000818:Animals; D017209:Apoptosis; D019521:Body Patterning; D002454:Cell Differentiation; D003743:Dental Enamel / Q000002:abnormalities / Q000196:embryology; D004622:Embryo, Mammalian / Q000002:abnormalities; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008334:Mandible / Q000002:abnormalities / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009432:Neural Crest / Q000166:cytology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012886:Skull / Q000166:cytology; D014070:Tooth / Q000196:embryology* / Q000473:pathology; D014071:Tooth Abnormalities; D051153:Wnt Proteins / Q000378:metabolism
D053823:Hedgehog Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D018125:Receptors, Transforming Growth Factor beta; C465570:Shh protein, mouse; D051153:Wnt Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625842:Tgfbr1 protein, mouse; C045073:Cre recombinase; D019426:Integrases