Sfrp4 Is Required for Proper Dental Formation and Stem Cell Regulation

Our studies have established that loss-of-function mutations in the Wnt signaling antagonist <i>SFRP4</i> (Secreted Frizzled Related Protein 4) cause Pyle disease, a rare skeletal disease characterized by limb deformity. Pyle disease can also present with a number of dental conditions, including tooth decay and taurodontism. Aside from the sparse clinical descriptions of the tooth anomalies seen in Pyle disease, the role of Sfrp4 in teeth has not been investigated. Here we show that in adult mouse incisors, Sfrp4 is expressed in the mesenchymal and epithelial compartments and their derivatives as well in the developing apex of the molar roots, pulp, odontoblasts, and periodontal ligament. We report that <i>Sfrp4</i> deletion in mice leads to markedly shorter incisors, with reduced dentin mineral apposition and enamel volume. In addition, we find that <i>Sfrp4</i> deletion leads to a reduction in the root length and bifurcation height of the developing molars, both features of taurodontism. Rodent incisors grow continuously during the animal's lifetime, thanks to the maintenance and interactions of epithelial (EpSCs) and mesenchymal stem cells (MSCs) at their apex. As such, the mouse incisor is a powerful tool for studying adult stem cells, their interactions, and their regulation. Using this model, we found that <i>Sfrp4</i> deletion leads to a significant decrease in Gli1⁺ MSCs and in Ki67 levels in mesenchymal transient amplifying cells and preameloblasts. <i>Sfrp4</i>-null incisors have reduced type I collagen levels and altered amelogenin and Mmp20 secretion accompanied by changes in the enamel maturation stages. When incisor growth is accelerated by preventing occlusion through tooth clipping, <i>Sfrp4</i>-null incisors grow significantly slower than <i>wt</i> incisors do. Our study suggests a key role for Sfrp4 in the fast-growing teeth (incisors) and developing molars, where there is a need to balance the maintenance and differentiation of the stem cell niche.