title: Hex acts with beta-catenin to regulate anteroposterior patterning via a Groucho-related co-repressor and Nodal.
abstract: In Xenopus, the establishment of the anteroposterior axis involves two key signalling pathways, canonical Wnt and Nodal-related TGFbeta. There are also a number of transcription factors that feedback upon these pathways. The homeodomain protein Hex, an early marker of anterior positional information, acts as a transcriptional repressor, suppressing induction and propagation of the Spemman organiser while specifying anterior identity. We show that Hex promotes anterior identity by amplifying the activity of canonical Wnt signalling. Hex exerts this activity by inhibiting the expression of Tle4, a member of the Groucho family of transcriptional co-repressors that we identified as a Hex target in embryonic stem (ES) cells and Xenopus embryos. This Hex-mediated enhancement of Wnt signalling results in the upregulation of the Nieuwkoop centre genes Siamois and Xnr3, and the subsequent increased expression of the anterior endodermal marker Cerberus and other mesendodermal genes downstream of Wnt signalling. We also identified Nodal as a Hex target in ES cells. We demonstrate that in Xenopus, the Nodal-related genes Xnr1 and Xnr2, but not Xnr5 and Xnr6, are regulated directly by Hex. The identification of Nodal-related genes as Hex targets explains the ability of Hex to suppress induction and propagation of the organiser. Together, these results support a model in which Hex acts early in development to reinforce a Wnt-mediated, Nieuwkoop-like signal to induce anterior endoderm, and later in this tissue to block further propagation of Nodal-related signals. The ability of Hex to regulate the same targets in both Xenopus and mouse implies this model is conserved.
authors.affiliation: Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JQ, UK.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Zamparini
authors.forename: Tim
authors.initials: T
authors.lastname: Watts
authors.forename: Clare E
authors.initials: CE
authors.lastname: Gardner
authors.forename: Simon R
authors.initials: SR
authors.lastname: Tomlinson
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Johnston
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Brickman
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008957:Models, Genetic; D055457:Nodal Protein; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C526007:NODAL protein, human; D055457:Nodal Protein; C526008:Nodal protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin