Tel1/ETV6 specifies blood stem cells through the agency of VEGF signaling.
The regulation of stem cell ontogeny is poorly understood. We show that the leukemia-associated Ets transcription factor, Tel1/ETV6, specifies the first hematopoietic stem cells (HSCs) in the dorsal aorta (DA). In contrast, Tel1/ETV6 has little effect on embryonic blood formation, further distinguishing the programming of the long- and short-term blood populations. Consistent with the notion of concordance of arterial and HSC programs, we show that Tel1/ETV6 is also required for the specification of the DA as an artery. We further show that Tel1/ETV6 acts by regulating the transcription of VegfA in both the lateral plate mesoderm and also in the somites. Exogenous VEGFA rescues Tel1/ETV6 morphants, and depletion of VEGFA or its receptor, Flk1, largely phenocopies Tel1/ETV6 depletion. Few such links between intrinsic and extrinsic programming of stem cells have been reported previously. Our data place Tel1/ETV6 at the apex of the genetic regulatory cascade leading to HSC production.
Ciau-Uitz
Aldo
A
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
Pinheiro
Philip
P
Gupta
Rajeev
R
Enver
Tariq
T
Patient
Roger
R
D001773:Blood Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D055018:Hemangioblasts / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D017403:In Situ Hybridization; D008648:Mesoderm / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010641:Phenotype; D050783:Proto-Oncogene Proteins c-ets / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction; D019170:Somites / Q000378:metabolism; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D000097764:ETS Translocation Variant 6 Protein