Indian hedgehog gene is a target of the bone morphogenetic protein signaling pathway.
Bone morphogenetic proteins (BMPs), a large subgroup of the transforming growth factor-beta family of growth factors, are key mediators of many fundamental processes in embryonic development. The BMP target genes mediating these effects and the mechanism of their selective regulation are poorly characterized. In this study, we used a chromatin immunoprecipitation-based gene cloning method to identify BMP target genes in a mouse embryonic carcinoma cell line. We identified the Indian hedgehog (Ihh) gene as a target of BMP signaling. Both reporter and reverses transcription-PCR assays revealed that Ihh is up-regulated in embryonic cells upon BMP treatment. The BMP response element of the Ihh promoter contains multiple GC-rich motifs known as the "Mad/Medea binding box" found in the Drosophila tinman gene and in the mouse Id1 gene. DNA binding studies revealed that Smad4 binds to these GC-rich motifs. These findings indicate that BMP stimulates Ihh expression. We also suggest expression of the Ihh gene, which contains multiple Smad binding sites, might be finely regulated by a gradient of BMP concentrations.
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Kenji
K
Seki
Akiko
A
Hata
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D020862:GC Rich Sequence; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D011485:Protein Binding; D011994:Recombinant Proteins / Q000494:pharmacology; D020218:Response Elements; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta; D015854:Up-Regulation / Q000187:drug effects
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D011994:Recombinant Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta