title: The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity.
abstract: Hematopoietic stem cell (HSC) development is regulated by several signaling pathways and a number of key transcription factors, which include Scl/Tal1, Runx1, and members of the Smad family. However, it remains unclear how these various determinants interact. Using a genome-wide computational screen based on the well characterized Scl +19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice. Smad6, Bmp4, and Runx1 transcripts are concentrated along the ventral aspect of the E10.5 dorsal aorta in the aorta-gonad-mesonephros region from which HSCs originate. Moreover, Smad6, an inhibitor of Bmp4 signaling, binds and inhibits Runx1 activity, whereas Smad1, a positive mediator of Bmp4 signaling, transactivates the Runx1 promoter. Taken together, our results integrate three key determinants of HSC development; the Scl transcriptional network, Runx1 activity, and the Bmp4/Smad signaling pathway.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Donaldson
authors.forename: Marella F T R
authors.initials: MF
authors.lastname: de Bruijn
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinston
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.forename: Liz
authors.initials: L
authors.lastname: Huckle
authors.forename: Sandie
authors.initials: S
authors.lastname: Piltz
authors.forename: Josette-Renée
authors.initials: JR
authors.lastname: Landry
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: David
authors.initials: D
authors.lastname: Tannahill
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D017124:Conserved Sequence; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D005810:Multigene Family; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction; D051905:Smad6 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D051905:Smad6 Protein; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse