A Sox2‐Lef‐1 Protein Interaction Inhibits Lef‐1 Transcriptional Activity and WNT Signaling During Odontogenesis

Tooth development proceeds through a series of steps wherein epithelial and mesenchymal tissue layers cooperate to form a tooth bud, and cells in the tooth bud are organized and differentiated into a mature tooth. Throughout this process, the changes in gene expression that are required for tooth formation are prompted by transcription factors. Lef‐1 is a transcription factor and a major effector of WNT signaling, and the loss of Lef‐1 expression or an ectopic increase in Lef‐1 results in dramatic dental anomalies in mice. The transcriptional mechanisms responsible for maintaining appropriate levels of Lef‐1 expression and downstream targets are not well understood. We show that Sox2, a major regulator of dental stem cells inhibits Lef‐1 transcriptional activation. Endogenous Sox2 directly binds to Lef‐1 and we have identified specific motifs in the Sox2 and Lef‐1 proteins regulating this interaction. By immobilizing different GST‐labeled Sox2 domains we show that the HMG domain of Sox2 is required for the Sox2‐Lef1 protein interaction. Functionally, Sox2 is capable of disrupting the association of Lef‐1 protein with its consensus DNA binding sequence. Taken together, these data suggest a novel mechanism wherein the Sox2 protein functions to negatively regulate the expression of Lef‐1 and Lef‐1 target genes during odontogenisis. These new mechanisms may also regulate other epithelial organs during development. Support or Funding Information Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA.