title: A novel mechanism for the transcriptional regulation of Wnt signaling in development.
abstract: 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.
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California 92037, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Vacik
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stubbs
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
mesh_terms: D000818:Animals; D005075:Biological Evolution; D017124:Conserved Sequence; D005123:Eye / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D029867:Xenopus Proteins; C544896:tcf7l2 protein, Xenopus; C492361:vax2 protein, Xenopus