Abstract
Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation.
Highlights
Odontomas are classified as odontogenic benign tumors, comprising odontogenic epithelium and odontogenic ectomesenchyme with disorganized dental hard tissue formation in the World Health Organization (WHO) Classification of Head and Neck Tumours[1]; these are thought to be developmental anomalies of tooth germ, such as hamartomas, rather than benign neoplasms
To examine whether the β-catenin pathway is activated in odontomas, the expression pattern of β-catenin was investigated in the remaining odontogenic epithelial cells within human odontomas specimens by using immunohistochemical analyses
To elucidate whether the activation of the β-catenin pathway was associated with genetic mutations of the CTNNB1 (β-catenin) gene or the adenomatous polyposis coli (APC) gene, genomic DNA from the two odontoma specimens with accumulation of β-catenin in nucleus/cytoplasm pattern (Fig. 1, left panels and Fig. S1b, left panels) was subjected to direct sequencing of exon 3 of the CTNNB1 gene, or of exon 15 of the APC gene
Summary
Odontomas are classified as odontogenic benign tumors, comprising odontogenic epithelium and odontogenic ectomesenchyme with disorganized dental hard tissue formation in the World Health Organization (WHO) Classification of Head and Neck Tumours[1]; these are thought to be developmental anomalies of tooth germ, such as hamartomas, rather than benign neoplasms. Several possible factors are shown to be involved in odontoma development (e.g., heredity, genetic mutations and trauma during primary dentition)[3], definitive mechanisms in the induction of odontomas remain to be clarified. It was reported that activation of the β-catenin pathway in SOX2-positive cells, which were thought to be odontogenic epithelial stem cells[19,20], was involved in odontomas[21] These studies revealed the importance of the β-catenin pathway in developmental anomalies such as odontomas, the precise function of the β-catenin pathway in odontogenic epithelial cells or in tooth germ development remains unclear. We investigated the activation of the β-catenin pathway in the remaining epithelial cells within human odontomas and the function of its pathway to control cellular growth through regulating gene expression in both odontogenic epithelial cells and tooth germ development
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