title: LEF1 is a critical epithelial survival factor during tooth morphogenesis.
abstract: LEF1 is a cell-type-specific transcription factor and mediates Wnt signaling pathway by association with its co-activator beta-catenin. Wnt signaling is known to be critical for the specification of cranial neural crest (CNC) cells and may regulate the fate diversity of the CNC during craniofacial morphogenesis. Loss of Lef1 results in arrested tooth development at the late bud stage and LEF1 is required for a relay of a Wnt signaling to a cascade of FGF signaling activities to mediate the epithelial-mesenchymal interaction during tooth morphogenesis. It remains unclear, however, what is the cellular mechanism of LEF1 signaling in regulating tooth morphogenesis. To test the hypothesis that LEF1 signaling regulates the fate of the dental epithelial and the CNC-derived mesenchymal cells during tooth morphogenesis, we investigated and compared the cellular migration, proliferation, and apoptotic activity within the tooth germ between the wild-type and Lef1 null mutant mice. Using the Wnt1-Cre/R26R transgenic system for indelibly marking the progenies of CNC cells, we show that there is no CNC migration defect in the Lef1 null mutant mice, indicating that the arrest in tooth development is not the result of shortage of the CNC contribution into the first branchial arch in the Lef1 mutant. Furthermore, there is no alteration in cell proliferation or condensation of the CNC-derived dental mesenchyme in the Lef1 null mutant, suggesting that LEF1 may not affect the cell cycle progression of the multipotential CNC cells during tooth morphogenesis. Importantly, apoptotic activity is significantly increased within the dental epithelium in the Lef1 null mutant mice. As the result of this increased cell death, the bud stage tooth germ fails to advance to the cap stage in the absence of Lef1. Inhibition of apoptotic activity by FGF4 rescues the tooth development in the Lef1 null mutant. Our studies suggest that LEF1 is a critical survival factor for the dental epithelial cells during tooth morphogenesis.
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: Xun
authors.initials: X
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Pablo
authors.initials: P
authors.lastname: Bringas
authors.forename: Takeyasu
authors.initials: T
authors.lastname: Maeda
authors.forename: Harold C
authors.initials: HC
authors.lastname: Slavkin
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.forename: Yang
authors.initials: Y
authors.lastname: Chai
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004848:Epithelium / Q000196:embryology; D005260:Female; D017403:In Situ Hybridization; D051821:Lymphoid Enhancer-Binding Factor 1; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D009432:Neural Crest / Q000166:cytology / Q000196:embryology; D009805:Odontogenesis / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D015398:Signal Transduction; D014070:Tooth / Q000196:embryology*; D014083:Tooth Germ / Q000166:cytology / Q000196:embryology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D014157:Transcription Factors