title: FGF signalling restricts haematopoietic stem cell specification via modulation of the BMP pathway.
abstract: Haematopoietic stem cells (HSCs) are produced during embryogenesis from the floor of the dorsal aorta. The localization of HSCs is dependent on the presence of instructive signals on the ventral side of the vessel. The nature of the extrinsic molecular signals that control the aortic haematopoietic niche is currently poorly understood. Here we demonstrate a novel requirement for FGF signalling in the specification of aortic haemogenic endothelium. Our results demonstrate that FGF signalling normally acts to repress BMP activity in the subaortic mesenchyme through transcriptional inhibition of bmp4, as well as through activation of two BMP antagonists, noggin2 and gremlin1a. Taken together, these findings demonstrate a key role for FGF signalling in establishment of the developmental HSC niche via its regulation of BMP activity in the subaortic mesenchyme. These results should help inform strategies to recapitulate the development of HSCs in vitro from pluripotent precursors.
authors.affiliation: 1] Department of Cellular and Molecular Medicine, Section of Cell and Developmental Biology, University of California, La Jolla, San Diego, California 92093, USA [2] MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 9DS, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Pouget
authors.affiliation: MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 9DS, UK.
authors.forename: Tessa
authors.initials: T
authors.lastname: Peterkin
authors.affiliation: MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 9DS, UK.
authors.forename: Filipa Costa
authors.initials: FC
authors.lastname: Simões
authors.affiliation: Department of Cellular and Molecular Medicine, Section of Cell and Developmental Biology, University of California, La Jolla, San Diego, California 92093, USA.
authors.forename: Yoonsung
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Cellular and Molecular Medicine, Section of Cell and Developmental Biology, University of California, La Jolla, San Diego, California 92093, USA.
authors.forename: David
authors.initials: D
authors.lastname: Traver
authors.affiliation: MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 9DS, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: Patient
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D004730:Endothelium, Vascular / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D042461:Vascular Endothelial Growth Factor A; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; C505202:grem1a protein, zebrafish; D005346:Fibroblast Growth Factors