Mesenchymal Sufu Regulates Development of Mandibular Molars via Shh Signaling.

Sonic hedgehog () in dental epithelium regulates tooth morphogenesis by epithelial-mesenchymal signaling transduction. However, the action of Shh signaling regulation in this process is not well understood. Here we find that mesenchymal Suppressor of Fused (), a major negative regulator of Shh signaling, plays an important role in modulating the tooth germ morphogenesis during the bud-to-cap stage transition. Deletion of in dental mesenchyme by mice leads to delayed development of mandibular molar into cap stage with defect of primary enamel knot (EK) formation. We show the disruption of cell proliferation and programmed cell death in dental epithelium and mesenchyme in mutants. Epithelial-specific adhesion molecule E-cadherin is evidently reduced in the bilateral basal cells of tooth germ at E14.5. The cells in the presumptive EK, predominantly expressing P-cadherin, appear stratified but fail to condense. Moreover, the transcripts of primary EK marker genes, including , and , are significantly decreased compared to controls. In contrast, we find that deficiency of results in elevation of Shh signaling in mesenchyme, indicated by the significant upregulation of and . Meanwhile, the expression of and , the critical factors of mesenchymal-epithelial induction, is significantly inhibited in dental mesenchyme. Furthermore, the expression of experiences a transient decrease at the bud stage. Taken together, these data suggest that mesenchymal is necessary for tuning the Shh signaling, which may act as an upstream modulator of and to coordinate the interplay between the dental mesenchyme and epithelium of tooth germ.