title: Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche.
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, we report that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizing VEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure to exogenous E2 during vascular niche development significantly 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.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kelli J
authors.initials: KJ
authors.lastname: Carroll
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Esain
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maija K
authors.initials: MK
authors.lastname: Garnaas
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Dovey
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Nissim
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Frechette
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Kwan
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Cutting
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Harris
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Gorelick
authors.affiliation: Carnegie Institution for Science, Baltimore, MD 21218, USA.
authors.forename: Marnie E
authors.initials: ME
authors.lastname: Halpern
authors.affiliation: University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Lawson
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: wgoessling@partners.org.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001559:Benzhydryl Compounds / Q000494:pharmacology; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis; D036388:Ephrin-B2 / Q000037:antagonists & inhibitors; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000494:pharmacology; D000077267:Fulvestrant; D019833:Genistein / Q000494:pharmacology; D018869:Heat-Shock Response; D055018:Hemangioblasts / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D060172:Morpholinos / Q000235:genetics; D010636:Phenols / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011959:Receptors, Estradiol / Q000235:genetics; D051880:Receptors, Notch / Q000096:biosynthesis; D015398:Signal Transduction; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000098826:Bisphenol A Compounds
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001559:Benzhydryl Compounds; D050676:Core Binding Factor Alpha 2 Subunit; D036388:Ephrin-B2; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D004997:Ethinyl Estradiol; D000077267:Fulvestrant; D019833:Genistein; D060172:Morpholinos; D010636:Phenols; D011518:Proto-Oncogene Proteins; D011959:Receptors, Estradiol; D051880:Receptors, Notch; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D029961:Zebrafish Proteins; C583604:Vegfaa protein, zebrafish; C472526:runx1 protein, zebrafish; C489367:tal1 protein, zebrafish; C006780:bisphenol A; D000098826:Bisphenol A Compounds