Transcription Factor Zic2 Inhibits Wnt/β-Catenin Protein Signaling

Pourebrahim, Rasoul; Houtmeyers, Rob; Ghogomu, Stephen Mbigha; Janssens, Sylvie; Thélie, Aurore; Tran, Hong Thi; Langenberg, Tobias; Vleminckx, Kris; Bellefroid, Éric; Cassiman, Jean Jacques; Tejpar, Sabine

doi:10.1074/jbc.m111.242826

Cited by 77 publications

(79 citation statements)

References 44 publications

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“…These results indicate that the ability of the nTFs to induce early neural genes in epidermal precursors is direct rather than the result of ectopic dorsal mesoderm formation. This conclusion is consistent with reports that each of the nTFs has been associated with either an anti-BMP or anti-Wnt activity (Kroll et al, 1998; Yan et al, 2009; Yan et al, 2010; Pourebrahim et al, 2011; Fujimi et al, 2012). …”

Section: Resultssupporting

confidence: 93%

Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm

Gaur

Mandelbaum

Herold

et al. 2016

Genesis

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The decision by embryonic ectoderm to give rise to epidermal versus neural derivatives is the result of signaling events during blastula and gastrula stages. However, there also is evidence in Xenopus that cleavage stage blastomeres contain maternally derived molecules that bias them toward a neural fate. We used a blastomere explant culture assay to test whether maternally deposited transcription factors bias 16-cell blastomere precursors of epidermal or neural ectoderm to express early zygotic neural genes in the absence of gastrulation interactions or exogenously supplied signaling factors. We found that Foxd4l1, Zic2, Gmnn and Sox11 each induced explants made from ventral, epidermis-producing blastomeres to express early neural genes, and that at least some of the Foxd4l1 and Zic2 activity is required at cleavage stages. Similarly, providing extra Foxd4l1 or Zic2 to explants made from dorsal, neural plate-producing blastomeres significantly increased expression of early neural genes, whereas knocking down either significantly reduced them. These results show that maternally delivered transcription factors bias cleavage stage blastomeres to a neural fate. We demonstrate that mouse and human homologues of Foxd4l1 have similar functional domains compared to the frog protein, as well as conserved transcriptional activities when expressed in Xenopus embryos and blastomere explants.

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Section: Resultssupporting

confidence: 93%

Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm

Gaur

Mandelbaum

Herold

et al. 2016

Genesis

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“…This suggests that SYS-1 blocks the activity of the REF-2:POP-1 complex. Interestingly, a recent study in vertebrates (Pourebrahim et al, 2011) has shown that Zic2, TCF4 and β-catenin can form a Zic:TCF:β-catenin trimolecular complex (β-catenin binding to the N-terminal domain of TCF and Zic binding to the HMG domain of TCF), and that this trimolecular complex is not able to activate transcription on TCF binding sites. This suggests that in C. elegans SYS-1/β-catenin could block the activity of the REF-2:POP-1 complex in the posterior daughter by binding to the POP-1 N-terminal domain.…”

Section: Resultsmentioning

confidence: 99%

“…The activation of REF-2 by POP-1 is blocked in the posterior daughter by SYS-1. While we have not analyzed in detail the mechanism of this blockage by SYS-1, a study in vertebrates has shown that Zic2 can directly bind a TCF4:β-catenin complex on TCF binding sites blocking transcriptional activation by TCF4:β-catenin (Pourebrahim et al, 2011). One possible mechanism is therefore that in the NB SIAD/SIBV neuroblast SYS-1 blocks the activation of ttx-3 expression by binding to the REF-2:POP-1 complex blocking its ability to activate transcription.…”

Section: Discussionmentioning

confidence: 99%

Atypical Transcriptional Activation by TCF via a Zic Transcription Factor in C. elegans Neuronal Precursors

et al. 2015

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Summary Transcription factors of the TCF family are key mediators of the Wnt/β-catenin pathway. TCF usually activates transcription on cis-regulatory elements containing TCF binding sites when the pathway is active and represses transcription when the pathway is inactive. However, some direct targets display an opposite regulation (activated by TCF in the absence of Wnt) but the mechanism behind this atypical regulation remains poorly characterized. Here we use the cis-regulatory region of an opposite target gene, ttx-3, to dissect the mechanism of this atypical regulation. Using a combination of genetic, molecular and biochemical experiments we establish that, in the absence of Wnt pathway activation, TCF activates ttx-3 expression via a Zic binding site by forming a complex with a Zic transcription factor. This mechanism is later reinforced by specific bHLH factors. This study reveals an atypical mode of action for TCF that may apply to other binary decisions mediated by Wnt signaling.

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“…The human ZIC2 and Xenopus zic1-5 proteins have recently been shown to act as cofactors that inhibit Wnt-dependent-β-catenin-mediated transcription (Pourebrahim et al, 2011; Fujimi et al, 2012). Upon Wnt stimulation, β-catenin enters the nucleus and interacts with the TCF transcription factors to stimulate transcription of target genes (Behrens et al, 1996).…”

Section: Resultsmentioning

confidence: 99%

“…The TOPflash and FOPflash vectors contain four optimal TCF binding sites or four mutant TCF binding sites, respectively, upstream of a minimal c-Fos promoter and luciferase cDNA. These vectors and the pCAN-β-catenin-ΔN89 expression construct (Munemitsu et al, 1996) were a gift from Sabine Tejpar (Molecular Digestive Oncology, Katholieke Universiteit Leuven, Belgium) (Pourebrahim et al, 2011). …”

Section: Methodsmentioning

confidence: 99%

A murineZic3transcript with a premature termination codon evades nonsense-mediated decay during axis formation

Ahmed

Ali

Warr

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYThe ZIC transcription factors are key mediators of embryonic development and ZIC3 is the gene most commonly associated with situs defects (heterotaxy) in humans. Half of patient ZIC3 mutations introduce a premature termination codon (PTC). In vivo, PTC-containing transcripts might be targeted for nonsense-mediated decay (NMD). NMD efficiency is known to vary greatly between transcripts, tissues and individuals and it is possible that differences in survival of PTC-containing transcripts partially explain the striking phenotypic variability that characterizes ZIC3-associated congenital defects. For example, the PTC-containing transcripts might encode a C-terminally truncated protein that retains partial function or that dominantly interferes with other ZIC family members. Here we describe the katun (Ka) mouse mutant, which harbours a mutation in the Zic3 gene that results in a PTC. At the time of axis formation there is no discernible decrease in this PTC-containing transcript in vivo, indicating that the mammalian Zic3 transcript is relatively insensitive to NMD, prompting the need to re-examine the molecular function of the truncated proteins predicted from human studies and to determine whether the N-terminal portion of ZIC3 possesses dominant-negative capabilities. A combination of in vitro studies and analysis of the Ka phenotype indicate that it is a null allele of Zic3 and that the N-terminal portion of ZIC3 does not encode a dominant-negative molecule. Heterotaxy in patients with PTC-containing ZIC3 transcripts probably arises due to loss of ZIC3 function alone.

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Transcription Factor Zic2 Inhibits Wnt/β-Catenin Protein Signaling

Cited by 77 publications

References 44 publications

Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm

Neural transcription factors bias cleavage stage blastomeres to give rise to neural ectoderm

Atypical Transcriptional Activation by TCF via a Zic Transcription Factor in C. elegans Neuronal Precursors

A murineZic3transcript with a premature termination codon evades nonsense-mediated decay during axis formation

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