title: Tbx1 is necessary for palatal elongation and elevation.
abstract: The transcription factor TBX1 is a key mediator of developmental abnormalities associated with DiGeorge/Velocardiofacial Syndrome. Studies in mice have demonstrated that decreased dosage of Tbx1 results in defects in pharyngeal arch, cardiovascular, and craniofacial development. The role of Tbx1 in cardiac development has been intensely studied; however, its role in palatal development is poorly understood. By studying the Tbx1-/- mice we found defects during the critical points of palate elongation and elevation. The intrinsic palate defects in the Tbx1-/- mice were determined by measuring changes in palate shelf length, proliferation, apoptosis, expression of relevant growth factors, and in palate fusion assays. Tbx1-/- embryos exhibit cleft palate with failed palate elevation in 100% and abnormal palatal-oral fusions in 50%. In the Tbx1-/- mice the palate shelf length was reduced and tongue height was greater, demonstrating a physical impediment to palate elevation and apposition. In vitro palate fusion assays demonstrate that Tbx1-/- palate shelves are capable of fusion but a roller culture assay showed that the null palatal shelves were unable to elongate. Diminished hyaluronic acid production in the Tbx1-/- palate shelves may explain failed palate shelf elevation. In addition, cell proliferation and apoptosis were perturbed in Tbx1-/- palates. A sharp decrease of Fgf8 expression was detected in the Tbx1-/- palate shelves, suggesting that Fgf8 is dependent on Tbx1 in the palate. Fgf10 is also up-regulated in the Tbx1-/- palate shelves and tongue. These data demonstrate that Tbx1 is a critical transcription factor that guides palatal elongation and elevation and that Fgf8 expression in the palate is Tbx1-dependent.
authors.affiliation: Department of Otolaryngology, Vanderbilt University School of Medicine, Nashville, TN, USA. steven.l.goudy@vanderbilt.edu <steven.l.goudy@vanderbilt.edu>
authors.forename: Steven
authors.initials: S
authors.lastname: Goudy
authors.forename: Amy
authors.initials: A
authors.lastname: Law
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sanchez
authors.forename: H Scott
authors.initials: HS
authors.lastname: Baldwin
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002972:Cleft Palate / Q000235:genetics*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006820:Hyaluronic Acid / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010159:Palate / Q000196:embryology* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism
chemical_list: C496457:Fgf8 protein, mouse; D051526:Fibroblast Growth Factor 10; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D053782:Transforming Growth Factor beta3; D051524:Fibroblast Growth Factor 8; D006820:Hyaluronic Acid