PUBLICATION

ETS transcription factor Etsrp / Etv2 is required for lymphangiogenesis and directly regulates vegfr3 / flt4 expression

Authors
Davis, J.A., Koenig, A.L., Lubert, A., Chestnut, B., Liu, F., Desai, S.P., Winkler, T., Pociute, K., Choi, K., Sumanas, S.
ID
ZDB-PUB-180513-11
Date
2018
Source
Developmental Biology   440(1): 40-52 (Journal)
Registered Authors
Desai, Sharina Palencia, Sumanas, Saulius
Keywords
ETS transcription factors, Etsrp, Etv2, Flt4, Vegfc, Vegfr3, lymphangiogenesis, lymphatics, thoracic duct, zebrafish
MeSH Terms
  • Vascular Endothelial Growth Factor C/genetics
  • Animals
  • Signal Transduction
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/physiology*
  • Endothelial Cells/metabolism
  • Morpholinos/metabolism
  • Lymphatic Vessels/embryology
  • Lymphatic Vessels/metabolism
  • Humans
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Embryonic Stem Cells
  • Gene Expression Regulation, Developmental/genetics
  • HEK293 Cells
  • Transcription Factors/genetics
  • Transcription Factors/physiology
  • Embryo, Nonmammalian
  • Zebrafish
  • Mice
  • Cell Differentiation
  • Lymphangiogenesis/genetics
  • Lymphangiogenesis/physiology*
(all 22)
PubMed
29753018 Full text @ Dev. Biol.
Abstract
The molecular mechanisms initiating the formation of the lymphatic system, lymphangiogenesis, are still poorly understood. Here we have identified a novel role in lymphangiogenesis for an ETS transcription factor, Etv2/Etsrp, a known regulator of embryonic vascular development. Through the use of fully validated photoactivatable morpholinos we show that inducible Etv2 inhibition in zebrafish embryos at 1day post-fertilization (dpf) results in significant inhibition of lymphangiogenesis, while development of blood vessels is unaffected. In Etv2-inhibited embryos and larvae, the number of lymphatic progenitors is greatly reduced, the major lymphatic vessel, the thoracic duct, is absent or severely fragmented, and lymphangiogenesis-associated marker expression, including lyve1b, prox1a, and vegfr3/flt4, is strongly downregulated. We also demonstrate that lymphatic progenitors in Etv2 deficient embryos fail to respond to Vegfc signaling. Chromatin immunoprecipitation and sequencing (ChIP-Seq) studies using differentiated mouse embryonic stem (ES) cells as well as luciferase reporter studies in the ES cells and in zebrafish embryos argue that Etv2 directly binds the promoter/enhancer regions of Vegfc receptor Vegfr3/Flt4 and lymphatic marker Lyve1, and promotes their expression. Together these data support a model where Etv2 initiates lymphangiogenesis by directly promoting the expression of flt4 within the posterior cardinal vein.
Genes / Markers
Figures
Figure Gallery (13 images) / 2
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ci1TgTransgenic Insertion
    ci5TgTransgenic Insertion
      ci29TgTransgenic Insertion
        nim5TgTransgenic Insertion
          nkuasgfp1aTgTransgenic Insertion
            y1TgTransgenic Insertion
              y11
                Insertion
                zf372TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  etsrpMO2-etsrpMRPHLNO
                  1 - 1 of 1
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                  Fish
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  KALTA4EFGKALTA4
                  mCherryEFGmCherry
                  TagRFPEFGTagRFP
                  1 - 4 of 4
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                  Mapping
                  No data available