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PITX2 and ß-Catenin Interactions Regulate Lef-1 Isoform Expression

Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas,¹ Department of Anatomy and Cell Biology, University of Iowa College of Medicine, Iowa City, Iowa,² Department of Biological Science, The University of Tulsa, Tulsa, Oklahoma,³ Escuela de Medicina, Tecnologico De Monterrey, Monterrey, Mexico⁴

Received 21 February 2007/ Returned for modification 9 May 2007/ Accepted 20 August 2007

Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with ß-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and ß-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length ß-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated ß-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and ß-catenin in which the Lef-1 ß-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, ß-catenin interacts with the PITX2 homeodomain and Lef-1 interacts with the PITX2 C-terminal tail. Lef-1 and ß-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and ß-catenin.

Published ahead of print on 4 September 2007.

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