Abstract
Transcription factor GATA4 regulates cardiac and osteoblast differentiation. However, its role in tooth development is not clear. Therefore, we generated Wnt1-Cre;GATA4fl/fl mice, with conditional inactivation of the GATA4 gene in the dental papilla mesenchymal cells. Phenotypic analysis showed short root deformity along with reduced expressions of odonto/osteogenic markers. Proliferation (but not apoptosis) of cells around the apical area of the root was attenuated. In vitro, we knocked down GATA4 expression in stem cells of dental apical papilla (SCAPs). Proliferation, migration and odonto/osteogenic differentiation of SCAPs were affected in the shGATA4 group. Overexpression of GATA4 in SCAPs increased mineralization. Based on our previous iTRAQ results, guanine nucleotide binding proteins 3 (GNAI3) is one of the distinct proteins after GATA4 deletion. G protein signaling is involved in bone development, remodeling, and disease. In this study, both GATA4 deletion in the mouse root and knock-down in human SCAPs decreased the expression of GNAI3. Dual-luciferase and ChIP assay confirmed the direct binding of GATA4 to the GNAI3 promoter, both in vitro and in vivo. GNAI3 knock-down significantly decreased the odonto/osteogenic differentiation ability of SCAPs. We thus establish the role of GATA4 as a novel regulator of root development and elucidate its downstream molecular events.
Highlights
Development of tooth root occurs after crown formation and the process involves reciprocal epithelio-mesenchymal interactions[1, 2]
The findings described here suggest that ablation of GATA binding protein 4 (GATA4) in the dental papilla mesenchymal cells resulted in the truncation of tooth root by disturbing the molecular expression
In the shGNAI3 group, the Alkaline Phosphatase (ALP)-positive area and the density of calcium nodes decreased significantly (Fig. 8L,M,N,O). These results suggest that GATA4 modulates odonto/osteogenic differentiation of SCAPs and that this effect is mediated via up-regulation of GNAI3 function
Summary
Development of tooth root occurs after crown formation and the process involves reciprocal epithelio-mesenchymal interactions[1, 2]. According to our own previous microarray results (unpublished data), GATA4 expression in the embryonic mouse maxillofacial tissues at embryo day 13.5 (E13.5) was significantly higher than that at E18.5 This result suggests a vital role of GATA4 in the development of the maxillofacial tissues. Wnt1-Cre;GATA4fl/fl mouse model with conditional knockout of GATA4 in the NCCs-derived dental papilla mesenchymal cells has been developed in this study. This mouse model has facilitated investigation of the role of GATA4 in the regulation of tooth root development. Our work indicates a novel role of GATA4 in regulating the proliferation and differentiation of dental mesenchymal cells during tooth development, and that this effect proceeds via GNAI3 expression. Our work showed that GNAI3 mediates these processes under the control of GATA4
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