title: GRG5/AES interacts with T-cell factor 4 (TCF4) and downregulates Wnt signaling in human cells and zebrafish embryos.
abstract: Transcriptional control by TCF/LEF proteins is crucial in key developmental processes such as embryo polarity, tissue architecture and cell fate determination. TCFs associate with β-catenin to activate transcription in the presence of Wnt signaling, but in its absence act as repressors together with Groucho-family proteins (GRGs). TCF4 is critical in vertebrate intestinal epithelium, where TCF4-β-catenin complexes are necessary for the maintenance of a proliferative compartment, and their abnormal formation initiates tumorigenesis. However, the extent of TCF4-GRG complexes' roles in development and the mechanisms by which they repress transcription are not completely understood. Here we characterize the interaction between TCF4 and GRG5/AES, a Groucho family member whose functional relationship with TCFs has been controversial. We map the core GRG interaction region in TCF4 to a 111-amino acid fragment and show that, in contrast to other GRGs, GRG5/AES-binding specifically depends on a 4-amino acid motif (LVPQ) present only in TCF3 and some TCF4 isoforms. We further demonstrate that GRG5/AES represses Wnt-mediated transcription both in human cells and zebrafish embryos. Importantly, we provide the first evidence of an inherent repressive function of GRG5/AES in dorsal-ventral patterning during early zebrafish embryogenesis. These results improve our understanding of TCF-GRG interactions, have significant implications for models of transcriptional repression by TCF-GRG complexes, and lay the groundwork for in depth direct assessment of the potential role of Groucho-family proteins in both normal and abnormal development.
authors.affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal. ltcosta@uevora.pt
authors.forename: Angela M Sousa
authors.initials: AM
authors.lastname: Costa
authors.forename: Isabel
authors.initials: I
authors.lastname: Pereira-Castro
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ricardo
authors.forename: Forrest
authors.initials: F
authors.lastname: Spencer
authors.forename: Shannon
authors.initials: S
authors.lastname: Fisher
authors.forename: Luís Teixeira
authors.initials: LT
authors.lastname: da Costa
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D060066:Protein Interaction Maps; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D056970:Co-Repressor Proteins; D012097:Repressor Proteins; C498445:TLE5 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C586153:tle5 protein, zebrafish