Abstract
Ligand-independent actions of the vitamin D receptor (VDR) are required for normal post-morphogenic hair cycles; however, the molecular mechanisms by which the VDR exerts these actions are not clear. Previous studies demonstrated impaired regulation of the canonical Wnt signaling pathway in primary keratinocytes lacking the VDR. To identify the key effector of canonical Wnt signaling that interacts with the VDR, GST pulldown studies were performed. A novel interaction between the VDR and LEF1 (lymphoid enhancer-binding factor-1) that is independent of β-catenin was identified. This interaction is dependent upon sequences within the N-terminal region of the VDR, a domain required for VDR-DNA interactions and normal hair cycling in mice. Mutation of specific residues within the N-terminal region of the VDR not only abrogated interactions between the VDR and LEF1 but also impaired the ability of the VDR to enhance Wnt signaling in vdr(-/-) primary keratinocytes. Thus, this study demonstrates a novel interaction between the VDR and LEF1 that is mediated by the DNA-binding domain of the VDR and that is required for normal canonical Wnt signaling in keratinocytes.