Intrinsic properties of Tcf1 and Tcf4 splice variants determine cell-type-specific Wnt/β-catenin target gene expression

Wallmen, Britta; Schrempp, Monika; Hecht, Andreas

doi:10.1093/nar/gks690

Cited by 39 publications

(44 citation statements)

References 69 publications

(127 reference statements)

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“…These results may also suggest that the β-catenin complex does not always increase histone acetylation, although it potentially has such an ability [55,56]. This is consistent with a recent study performed on embryonic stem cells, in which knockdown of Tcf7 and Tcf7l2 did not affect the active chromatin conformation of their targets [57]. We also noticed an interesting pattern of LEF1/TCF motif occurrence in the examined genes.…”

Section: Discussionsupporting

confidence: 91%

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

et al. 2012

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BackgroundLEF1/TCF transcription factors and their activator β-catenin are effectors of the canonical Wnt pathway. Although Wnt/β-catenin signaling has been implicated in neurodegenerative and psychiatric disorders, its possible role in the adult brain remains enigmatic. To address this issue, we sought to identify the genetic program activated by β-catenin in neurons. We recently showed that β-catenin accumulates specifically in thalamic neurons where it activates Cacna1g gene expression. In the present study, we combined bioinformatics and experimental approaches to find new β-catenin targets in the adult thalamus.ResultsWe first selected the genes with at least two conserved LEF/TCF motifs within the regulatory elements. The resulting list of 428 putative LEF1/TCF targets was significantly enriched in known Wnt targets, validating our approach. Functional annotation of the presumed targets also revealed a group of 41 genes, heretofore not associated with Wnt pathway activity, that encode proteins involved in neuronal signal transmission. Using custom polymerase chain reaction arrays, we profiled the expression of these genes in the rat forebrain. We found that nine of the analyzed genes were highly expressed in the thalamus compared with the cortex and hippocampus. Removal of nuclear β-catenin from thalamic neurons in vitro by introducing its negative regulator Axin2 reduced the expression of six of the nine genes. Immunoprecipitation of chromatin from the brain tissues confirmed the interaction between β-catenin and some of the predicted LEF1/TCF motifs. The results of these experiments validated four genes as authentic and direct targets of β-catenin: Gabra3 for the receptor of GABA neurotransmitter, Calb2 for the Ca2+-binding protein calretinin, and the Cacna1g and Kcna6 genes for voltage-gated ion channels. Two other genes from the latter cluster, Cacna2d2 and Kcnh8, appeared to be regulated by β-catenin, although the binding of β-catenin to the regulatory sequences of these genes could not be confirmed.ConclusionsIn the thalamus, β-catenin regulates the expression of a novel group of genes that encode proteins involved in neuronal excitation. This implies that the transcriptional activity of β-catenin is necessary for the proper excitability of thalamic neurons, may influence activity in the thalamocortical circuit, and may contribute to thalamic pathologies.

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Section: Discussionsupporting

confidence: 91%

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

et al. 2012

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“…Given that almost all invertebrate TCFs possess a conserved C-clamp, our data will be relevant to important family members such as POP-1 in C. elegans [52] and TCF in Hydra [53]. Likewise, the C-clamps in TCF1E and TCF4E isoforms probably have similar properties as we have uncovered in TCF/Pan, which likely contribute to the ability of these isoforms to activate specific Wnt targets [24], [26], [27], [45] and promote oncogenesis [24], [26]. Whether C-clamps from other proteins, e.g., GLUT4EF, can bind to the HMG domain of TCFs is another interesting question that requires further investigation.…”

Section: Discussionmentioning

confidence: 62%

Structure-Function Analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin Signaling

Ravindranath

Cadigan

2014

PLoS ONE

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The evolutionarily conserved Wnt/ß-catenin (Wnt/ß-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility Group (HMG) domain that bind specific DNA sequences. Invertebrate TCFs and some vertebrate TCF isoforms also contain another domain, called the C-clamp, which allows TCFs to recognize an additional DNA motif known as the Helper site. While the C-clamp has been shown to be important for regulating several Wnt reporter genes in cell culture, its physiological role in regulating Wnt targets is less clear. In addition, little is known about this domain, except that two of the four conserved cysteines are functionally important. Here, we carried out a systematic mutagenesis and functional analysis of the C-clamp from the Drosophila TCF/Pangolin (TCF/Pan) protein. We found that the C-clamp is a zinc-binding domain that is sufficient for binding to the Helper site. In addition to this DNA-binding activity, the C-clamp also inhibits the HMG domain from binding its cognate DNA site. Point mutations were identified that specifically affected DNA-binding or reduced the inhibitory effect. These mutants were characterized in TCF/Pan rescue assays. The specific DNA-binding activity of the C-clamp was essential for TCF/Pan function in cell culture and in patterning the embryonic epidermis of Drosophila, demonstrating the importance of this C-clamp activity in regulating Wnt target gene expression. In contrast, the inhibitory mutation had a subtle effect in cell culture and no effect on TCF/Pan activity in embryos. These results provide important information about the functional domains of the C-clamp, and highlight its importance for Wnt/ß-cat signaling in Drosophila.

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“…All TCF transcription factors bind to transcriptional corepressors, which are then displaced in response to accumulation of nuclear β-catenin (45,46). In response to WNT ligands, TCF transcription factors have varying abilities to control target gene expression based on cell type, epigenetic state, and TCF/LEF binding ability (47,48). For example, Axin2 shows less selectivity for specific TCF isoforms needed for WNT-induced transcription, whereas T/Bra is more stringent in its TCF-binding complement for WNT-induced transcription (48).…”

Section: Ctnnb1mentioning

confidence: 99%

“…In response to WNT ligands, TCF transcription factors have varying abilities to control target gene expression based on cell type, epigenetic state, and TCF/LEF binding ability (47,48). For example, Axin2 shows less selectivity for specific TCF isoforms needed for WNT-induced transcription, whereas T/Bra is more stringent in its TCF-binding complement for WNT-induced transcription (48). Interestingly, full-length TCF4, but not LEF1 or TCF3, induces MMP1, MMP3, and MMP13 expression in human chondrocytes in vitro and is upregulated in human OA cartilage compared with healthy cartilage in vivo (49).…”

Section: Ctnnb1mentioning

confidence: 99%

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

Rockel

Whetstone

et al. 2016

Journal of Clinical Investigation

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Intrinsic properties of Tcf1 and Tcf4 splice variants determine cell-type-specific Wnt/β-catenin target gene expression

Cited by 39 publications

References 69 publications

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability

Structure-Function Analysis of the C-clamp of TCF/Pangolin in Wnt/ß-catenin Signaling

Hedgehog inhibits β-catenin activity in synovial joint development and osteoarthritis

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