GRG5/AES Interacts with T-Cell Factor 4 (TCF4) and Downregulates Wnt Signaling in Human Cells and Zebrafish Embryos
- Authors
- Costa, A.M., Pereira-Castro, I., Ricardo, E., Spencer, F., Fisher, S., and da Costa, L.T.
- ID
- ZDB-PUB-130712-20
- Date
- 2013
- Source
- PLoS One 8(7): e67694 (Journal)
- Registered Authors
- Fisher, Shannon
- Keywords
- none
- MeSH Terms
-
- Gene Expression Regulation, Developmental
- Humans
- Up-Regulation
- Zebrafish/embryology*
- Repressor Proteins/genetics
- Repressor Proteins/metabolism*
- Co-Repressor Proteins/genetics
- Co-Repressor Proteins/metabolism*
- Wnt Proteins/genetics
- Wnt Proteins/metabolism*
- Signal Transduction
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Down-Regulation
- Protein Interaction Maps
- Transcriptional Activation*
- Transcription Factor 7-Like 2 Protein/chemistry
- Transcription Factor 7-Like 2 Protein/genetics
- Transcription Factor 7-Like 2 Protein/metabolism*
- beta Catenin/genetics
- beta Catenin/metabolism
- Amino Acid Motifs
- HEK293 Cells
- Animals
- PubMed
- 23840876 Full text @ PLoS One
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.
