Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche

Kelli J. Carroll, Virginie Esain, Maija K. Garnaas, Mauricio Cortes, Michael C. Dovey, Sahar Nissim, Gregory M. Frechette, Sarah Y. Liu, Wanda Kwan, Claire C. Cutting, James M. Harris, Daniel A. Gorelick, Marnie E. Halpern, Nathan D. Lawson, Wolfram Goessling, Trista E. North

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, wereport that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizingVEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure toexogenous E2 during vascular niche developmentsignificantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.

Original languageEnglish (US)
Pages (from-to)437-453
Number of pages17
JournalDevelopmental Cell
Volume29
Issue number4
DOIs
StatePublished - May 27 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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