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.

PITX2 and β-Catenin Interactions Regulate Lef-1 Isoform Expression

“…In Lef-1 mutant mice, tooth development is arrested at later stages, and the mice lack teeth. Consistent with this phenotype, Lef-1 expression can be seen at E10.5 in the dental epithelium, and at E14.5 during cap stage development, Lef-1 was found in both the dental epithelium and dental papilla mesenchyme (40,43). From E10 to E12, Lef-1 transcripts are detected initially in the epithelium and subsequently in the mesenchyme, consistent with the change in the developmental dominance of these tissues (34).…”

“…Lef-1 in the survival of dental epithelial cells during tooth development (40). In Lef-1-null mutant mice, the dental epithelium underwent increased apoptosis and subtle changes in cell proliferation.…”

Spatially restricted dental regeneration drives pufferfish beak development

“…4 C-G). These markers have previously been shown to play vital roles during differentiation and morphogenesis in other vertebrate dentitions (28)(29)(30)(31). We observed the expression of these four markers in a single banded unit associated with the continuous and elongated dental epithelium for each tooth generation, thus suggesting that each band represents a single, highly enlarged and elongated tooth and is not formed through the coalescence of multiple teeth across the jaw.…”

Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis

“…The first evidence for a crucial role of the Wnt pathway in odontogenesis comes from the functional analysis of Lef1. The protein product of this gene is a transcription factor that plays a role in activating Wnt target genes and it is also a critical factor affecting the survival of the epithelial cells during tooth morphogenesis (Sasaki et al 2005). Mice homozygous for the Lef1 deletion died shortly after birth and showed abnormalities in epithelial-mesenchymal interactions, which led to an arrest of tooth development at the bud stage (Kratochwil et al 1996).…”