ZFIN ID: ZDB-PUB-180513-11
ETS transcription factor Etsrp / Etv2 is required for lymphangiogenesis and directly regulates vegfr3 / flt4 expression
Davis, J.A., Koenig, A.L., Lubert, A., Chestnut, B., Liu, F., Desai, S.P., Winkler, T., Pociute, K., Choi, K., Sumanas, S.
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:
  • Animals
  • Cell Differentiation
  • Embryo, Nonmammalian
  • Embryonic Stem Cells
  • Endothelial Cells/metabolism
  • Gene Expression Regulation, Developmental/genetics
  • HEK293 Cells
  • Humans
  • Lymphangiogenesis/genetics
  • Lymphangiogenesis/physiology*
  • Lymphatic Vessels/embryology
  • Lymphatic Vessels/metabolism
  • Mice
  • Morpholinos/metabolism
  • Signal Transduction
  • Transcription Factors/genetics
  • Transcription Factors/physiology
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/physiology*
PubMed: 29753018 Full text @ Dev. Biol.
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.