TCF-4 binds β-catenin and is expressed in distinct regions of the embryonic brain and limbs

Department of Pathology and Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Mechanisms of Development (Impact Factor: 2.44). 10/1998; 77(1):9-18. DOI: 10.1016/S0925-4773(98)00131-2
Source: PubMed


The Tcf family of transcription factors, in association with beta-catenin, mediate Wnt signaling by transactivating downstream target genes. Given the function of wnt genes in neural development and organogenesis, Tcf transcription factors must be integral to the development of many embryonic tissues. In fact, the role of Tcf genes in axis formation in Xenopus and in segment polarity in Drosophila is well established. In this report, we have identified two isoforms of the mouse Tcf-4 gene. Tcf-4 expressing cells showed nuclear localization of beta-catenin. Although Tcf-4 RNA was widely distributed throughout embryogenesis, high levels of Tcf-4 expression were particularly evident in the developing CNS and limb buds. In extended streak stage embryos (E7.5), Tcf4 expression was detected in anterior endoderm. E8.5 embryos had Tcf-4 expression in rostral neural plate and in alternating rhombomeres of the hindbrain. By E9.5 and thereafter, expression in the hindbrain disappeared and strong expression was detected in the diencephalon. Strikingly Tcf-4 expression in the forebrain was undetected in Small eye mutant embryos indicating that Pax-6 is required for Tcf-4 expression in the forebrain. In developing limbs, Tcf-4 is readily detected starting at E10.5 and is limited to mesenchymal cells surrounding the areas of chondrification. These data indicate a function for Tcf-4 in neural and limb development, two tissues where Wnt signaling plays an essential role.

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Available from: Gregory Dressler
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    • "This result is particularly important because it was obtained in an unbiased way – in a cDNA library screen for TCF4 interacting proteins where GRG5/AES was the most frequently obtained candidate – and not through candidate testing. Additional support for an in vivo interaction between TCF4 and GRG5/AES comes from the overlapping expression patterns of these two proteins observed in several vertebrates [86,102–105] and the evidence for their critical roles during pituitary gland development [102]. "
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    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.
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    • "During embryonic development, Tcf7l2 is primarily expressed in the thalamic and pretectal neuroepithelial domains at early stages of vertebrate development. This expression is subsequently extended to the midbrain and other forebrain regions during early steps of the specification of postmitotic neuroepithelial cells in all studied vertebrates (Cho and Dressler 1998; Ferran et al. 2007; Bluske et al. 2009; Quinlan et al. 2009; Merchán et al. 2011; Morona et al. 2011). However, expression data are much scarcer for postnatal stages. "
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    • "It has been shown that, in Xenopus embryo, IGF-I is capable of regulating the expression of several Wnt mRNAs (Carron et al., 2005). To determine whether IGF signalling also can regulate the expression of other canonical Wnt signalling molecules in mouse brain, we quantified the abundance of mRNA for Wnt ligands, frizzled receptors and TCF-4 transcription factor, which are highly expressed in the CNS in a spatial-and temporal-specific pattern (Roelink and Nusse, 1991; Parr et al., 1993; Hollyday et al., 1995; Cho and Dressler, 1998). As shown in Figure 6, the mRNA abundance of the Wnt ligands and Frizzled receptors examined, except for Wnt 3a and Frizzled 3, was similar in the brain of E17.5 IGF1R Nestin2KO mice and control mice. "
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