title: TGFbeta-mediated FGF signaling is crucial for regulating cranial neural crest cell proliferation during frontal bone development.
abstract: The murine frontal bone derives entirely from the cranial neural crest (CNC) and consists of the calvarial (lateral) aspect that covers the frontal lobe of brain and the orbital aspect that forms the roof of bony orbit. TGFbeta and FGF signaling have important regulatory roles in postnatal calvarial development. Our previous study has demonstrated that conditional inactivation of Tgfbr2 in the neural crest results in severe defects in calvarial development, although the cellular and molecular mechanisms by which TGFbeta signaling regulates the fate of CNC cells during frontal bone development remain unknown. Here, we show that TGFbeta IIR is required for proliferation of osteoprogenitor cells in the CNC-derived frontal bone anlagen. FGF acts downstream of TGFbeta signaling in regulating CNC cell proliferation, and exogenous FGF2 rescues the cell proliferation defect in the frontal primordium of Tgfbr2 mutant. Furthermore, the CNC-derived frontal primordium requires TGFbeta IIR to undergo terminal differentiation. However, this requirement is restricted to the developing calvarial aspect of the frontal bone, whereas the orbital aspect forms despite the ablation of Tgfbr2 gene, implying a differential requirement for TGFbeta signaling during the development of various regions of the frontal bone. This study demonstrates the biological significance of TGFbeta-mediated FGF signaling cascade in regulating frontal bone development, suggests that TGFbeta functions as a morphogen in regulating the fate of the CNC-derived osteoblast and provides a model for investigating abnormal craniofacial development.
authors.affiliation: Center for Craniofacial Molecular Biology School of Dentistry University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Sasaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.forename: Pablo
authors.initials: P
authors.lastname: Bringas
authors.forename: Stanley
authors.initials: S
authors.lastname: Chou
authors.forename: Mark M
authors.initials: MM
authors.lastname: Urata
authors.forename: Harold
authors.initials: H
authors.lastname: Slavkin
authors.forename: Yang
authors.initials: Y
authors.lastname: Chai
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005624:Frontal Bone / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C501120:Dlx5 protein, mouse; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II