Figure 9.

ARS enamel defect model. (Upper panel) Schematic illustration of normal tooth development. During normal amelogenesis, the level of Hmgn2 expression decreases, leading to de-repression of Pitx2 and, consequently, activation of Amel expression, by both direct transcriptional activation and alteration of the transcriptional hierarchy that modulates Amel expression. The outcome is normal enamel deposition and mineralization. (Lower panel) Schematic illustration of the model for tooth development in ARS patients and in the context of Hmgn2 overexpression. When PITX2 loses its transcriptional function due to ARS mutations, both direct and indirect activation of Amel expression are perturbed, leading to decreased enamel deposition, and thus to a hypoplastic enamel layer. The K14-Hmgn2 transgenic mice, in which the high Hmgn2 levels lead to Pitx2 inhibition that mimics Pitx2 loss-of-function, phenocopy of the enamel hypoplasia observed in ARS patients. Red triangles, downregulation of expression; green triangles, upregulation of expression; DE, dental epithelium; FM, follicle mesenchyme; PM, papilla mesenchyme; Dt, dentin; Enm, enamel.