Fibroblast growth factor controls the timing of Scl, Lmo2, and Runx1 expression during embryonic blood development.
To program pluripotent cells into blood, a knowledge of the locations of precursors during their journey through the embryo and the signals they experience would be informative. The anterior (a) and posterior (p) ventral blood islands (VBIs) in Xenopus are derived from opposite sides of the pregastrula embryo. The aVBI goes through a "hemangioblast" state, characterized by coexpression of blood and endothelial genes at neurula stages, whereas the pVBI expresses these genes in a nonoverlapping fashion several hours later, after commitment to either a blood or an endothelial fate. We describe a novel role for fibroblast growth factor (FGF) in controlling the timing of Scl, Lmo2, and Runx1 expression in the 2 VBI compartments. Blocking FGF signaling during gastrulation expands expression at neurula stages into posterior regions. We show, by lineage labeling, explant analysis, and targeted blocking of FGF signaling, that this is due to the pVBI prematurely expressing these genes with the timing of the aVBI. In contrast, overexpression of FGF in aVBI precursors eliminates the anterior hemangioblast program. Using this information, we have recapitulated the anterior hemangioblast program in pluripotent cells in vitro by inhibiting FGF signaling in anterior mesoderm induced by activin and exposed to bone morphogenetic protein (BMP) signaling.
Walmsley
Maggie
M
Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Cleaver
David
D
Patient
Roger
R
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527518:Lmo2 protein, Xenopus; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; C489365:TAL1 protein, Xenopus; D014157:Transcription Factors; D029867:Xenopus Proteins; D005346:Fibroblast Growth Factors