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

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

Jennifer A. Davis, Andrew L. Koenig, Allison Lubert, Brendan Chestnut, Fang Liu, Sharina Palencia Desai, Tamara Winkler, Karolina Pociute, Kyunghee Choi and Saulius Sumanas
Developmental biology, Vol.440(1), pp.40-52
08/01/2018
DOI: 10.1016/j.ydbio.2018.05.003
PMCID: PMC6054491
PMID: 29753018

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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 1 day 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. •Etv2 expression is enriched in the vein during zebrafish lymphangiogenesis.•Inducible Etv2 knockdown inhibits lymphangiogenesis.•Blood vessels are not affected by Etv2 knockdown at 24 hpf.•Vegfc fails to induce lymphangiogenesis in Etv2 knockdown embryos.•Etv2 directly binds to Flt4 promoter and promotes its expression.
 ETS transcription factors Etsrp Etv2 Flt4 Lymphangiogenesis Lymphatics Thoracic duct Vegfc Vegfr3 Zebrafish

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