IADR Abstract Archives
A microRNA-26b- Lef-1 Gene Network Regulates Dental Stem Cells
Objectives: microRNAs (miRs) modulate gene expression during early craniofacial and tooth development. Lef-1 is an early transcription factor regulating dental epithelial progenitors and switching to mesenchymal regulation after E14.5 in the mouse. We asked if miR-26b over expression in mice regulated early dental epithelial progenitors and Lef-1 expression during tooth development.
Methods: miR-26b over-expression (OE) and Lef-1 conditional OE mice were generated to understand their roles during embryonic development. These mice were mated to generate a miR-26b/Lef-1 OE mouse. Histology, immunohistochemical, biochemical and molecular biology assays revealed new gene expression pathways that control dental stem cell proliferation and differentiation.
Results: The miR-26b over expression mice have craniofacial defects including a lack of incisors, molars and hair. miR-26b targets Lef-1 to modulate Lef-1 transcriptional activity. miR-26b expression correlates with the transition of Lef-1 expression in the dental epithelium to the dental mesenchyme. miR-26b regulates all Lef-1 isoforms and Wnt signaling, dependent on the Lef-1 isoform expressed in specific dental tissues. miR-26b acts to confine the dental epithelial stem cell niche to the LaCL and inhibits proliferation of the dental stem cell progenitors. Lef-1 OE expands the dental stem cell niche by activating stem cell factors and progenitor proliferation.
Conclusions: This is the first demonstration of a mouse model for miR regulation that has tooth agenesis. miR-26b regulation of Lef-1 is essential for normal tooth and craniofacial development. miR-26b over-expression mice have arrested early tooth development coincident with decreased epithelial progenitor cell proliferation. Inhibition of Lef-1 expression in the E14.5 dental epithelium by miR-26b is required to maintain the stem cell niche.
Methods: miR-26b over-expression (OE) and Lef-1 conditional OE mice were generated to understand their roles during embryonic development. These mice were mated to generate a miR-26b/Lef-1 OE mouse. Histology, immunohistochemical, biochemical and molecular biology assays revealed new gene expression pathways that control dental stem cell proliferation and differentiation.
Results: The miR-26b over expression mice have craniofacial defects including a lack of incisors, molars and hair. miR-26b targets Lef-1 to modulate Lef-1 transcriptional activity. miR-26b expression correlates with the transition of Lef-1 expression in the dental epithelium to the dental mesenchyme. miR-26b regulates all Lef-1 isoforms and Wnt signaling, dependent on the Lef-1 isoform expressed in specific dental tissues. miR-26b acts to confine the dental epithelial stem cell niche to the LaCL and inhibits proliferation of the dental stem cell progenitors. Lef-1 OE expands the dental stem cell niche by activating stem cell factors and progenitor proliferation.
Conclusions: This is the first demonstration of a mouse model for miR regulation that has tooth agenesis. miR-26b regulation of Lef-1 is essential for normal tooth and craniofacial development. miR-26b over-expression mice have arrested early tooth development coincident with decreased epithelial progenitor cell proliferation. Inhibition of Lef-1 expression in the E14.5 dental epithelium by miR-26b is required to maintain the stem cell niche.