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Genes Dev 2011 Sep 01;2517:1783-95. doi: 10.1101/gad.17227011.
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A novel mechanism for the transcriptional regulation of Wnt signaling in development.

Vacik T , Stubbs JL , Lemke G .

Axial patterning of the embryonic brain requires a precise balance between canonical Wnt signaling, which dorsalizes the nervous system, and Sonic hedgehog (Shh), which ventralizes it. The ventral anterior homeobox (Vax) transcription factors are induced by Shh and ventralize the forebrain through a mechanism that is poorly understood. We therefore sought to delineate direct Vax target genes. Among these, we identify an extraordinarily conserved intronic region within the gene encoding Tcf7l2, a key mediator of canonical Wnt signaling. This region functions as a Vax2-activated internal promoter that drives the expression of dnTcf7l2, a truncated Tcf7l2 isoform that cannot bind β-catenin and that therefore acts as a potent dominant-negative Wnt antagonist. Vax2 concomitantly activates the expression of additional Wnt antagonists that cooperate with dnTcf7l2. Specific elimination of dnTcf7l2 in Xenopus results in headless embryos, a phenotype consistent with a fundamental role for this regulator in forebrain development.

PubMed ID: 21856776
PMC ID: PMC3175715
Article link: Genes Dev
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: apc chrd ctbp1 ctnnb1 cyp26a1 en2 gsk3b hdac2 otx2 shh tbx2 tcf7l2 tle1 vax1 vax2
Morpholinos: tcf7l2 MO2 tcf7l2 MO3

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References [+] :
Angus-Hill, T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. 2011, Pubmed