title: Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5' enhancer and directs forebrain precursor development.
abstract: Development of the anterior forebrain precursor (AFBP) in the anterior neural plate (ANP) depends on the activation of the Hesx1 transcription factor gene. The Hesx1-expression domain of the ANP is underlain by Dkk1-expressing tissues, initially proximal-most anterior visceral endoderm (AVE), and later anterior mesendoderm (AME). As Dkk1-null embryos fail to develop the Hesx1-expressing domain, it is likely that Wnt signal inhibition in the ANP is required for the Hesx1 activation. To investigate the regulation of the AFBP development, we took advantage of epiblast stem cells (EpiSCs), which develop into the ANP in the absence of activin signaling. Expression of Hesx1 and Six3, both involved in the AFBP development, was strongly activated 2 days after activin removal and concomitant addition of Wnt signal inhibitors, Dkk1 or XAV939. Furthermore, we showed that activation of the 720-bp Hesx1 5' enhancer is responsible for Hesx1 expression in the AFBP and depends on Wnt signal inhibition. In addition, we showed that Wnt inhibition during the first day has larger impact on the activation of Hesx1 and Six3 than the second day, suggesting that in embryos Wnt inhibition caused by the AVE-derived Dkk1, rather than the AME-derived Dkk1, contributes greatly in the establishment of the AFBP.
authors: Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors: Kazunari
authors: K
authors: Matsuda
authors: Hisato
authors: H
authors: Kondoh
mesh_terms: D024506:5' Flanking Region; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000378:metabolism; D005855:Germ Layers / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016548:Prosencephalon / Q000196:embryology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D051153:Wnt Proteins / Q000378:metabolism*; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D000097607:Homeobox Protein SIX3; C501127:Dkk1 protein, mouse; C489733:Hesx1 protein, mouse