Tel1/ETV6 specifies blood stem cells through the agency of VEGF signaling

Dev Cell. 2010 Apr 20;18(4):569-78. doi: 10.1016/j.devcel.2010.02.009.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Cells / cytology*
  • ETS Translocation Variant 6 Protein
  • Gene Expression Regulation, Developmental*
  • Hemangioblasts / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Humans
  • In Situ Hybridization
  • Mesoderm / metabolism
  • Models, Biological
  • Models, Genetic
  • Molecular Sequence Data
  • Phenotype
  • Proto-Oncogene Proteins c-ets / physiology*
  • Repressor Proteins / physiology*
  • Signal Transduction
  • Somites / metabolism
  • Transcription, Genetic
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • Vascular Endothelial Growth Factor A

Associated data

  • GENBANK/EU760352