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TGIF (TG-interacting factor) represses transforming growth factor β (TGF-β)-activated gene expression and can repress transcription via a specific retinoid response element. Mutations in human TGIF are associated with holoprosencephaly, a severe defect of craniofacial development with both genetic and environmental causes. Both TGF-β and retinoic acid signaling are implicated in craniofacial development. Here, we analyze the role of TGIF in regulating retinoid responsive gene expression. We demonstrate that TGIF interacts with the ligand binding domain of the RXRα retinoid receptor and represses transcription from retinoid response elements. TGIF recruits the general corepressor, CtBP, to RXRα, and this recruitment is required for full repression by TGIF. Interaction between TGIF and RXRα is reduced by the addition of retinoic acid, consistent with a role for TGIF as an RXRα transcriptional corepressor. We …