Mir-126 is a conserved modulator of lymphatic development

Zacharias Kontarakis, Andrea Rossi, Sophie Ramas, Michael T. Dellinger, Didier Y.R. Stainier

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Organ homeostasis relies upon cellular and molecular processes that restore tissue structure and function in a timely fashion. Lymphatic vessels help maintain fluid equilibrium by returning interstitial fluid that evades venous uptake back to the circulation. Despite its important role in tissue homeostasis, cancer metastasis, and close developmental origins with the blood vasculature, the number of molecular players known to control lymphatic system development is relatively low. Here we show, using genetic approaches in zebrafish and mice, that the endothelial specific microRNA mir-126, previously implicated in vascular integrity, regulates lymphatic development. In zebrafish, in contrast to mir-126 morphants, double mutants (mir-126a-/-; mir-126b-/-, hereafter mir-126-/-) do not exhibit defects in vascular integrity but develop lymphatic hypoplasia; mir-126-/- animals fail to develop complete trunk and facial lymphatics, display severe edema and die as larvae. Notably, following MIR-126 inhibition, human Lymphatic Endothelial Cells (hLECs) respond poorly to VEGFA and VEGFC. In this context, we identify a concomitant reduction in Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) and Vascular Endothelial Growth Factor Receptor-3 (VEGFR3, also known as FLT4) expression upon MIR-126 inhibition. In vivo, we further show that flt4 +/- zebrafish embryos exhibit lymphatic defects after mild miR-126 knockdown. Similarly, loss of Mir-126 in Flt4 +/- mice results in embryonic edema and lethality. Thus, our results indicate that miR-126 modulation of Vegfr signaling is essential for lymphatic system development in fish and mammals.

Original languageEnglish (US)
JournalDevelopmental Biology
DOIs
StateAccepted/In press - Jan 1 2018

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Zebrafish
Lymphatic System
Blood Vessels
Edema
Homeostasis
Vascular Endothelial Growth Factor Receptor-3
Vascular Endothelial Growth Factor Receptor-2
Lymphatic Vessels
Extracellular Fluid
MicroRNAs
Larva
Mammals
Fishes
Embryonic Structures
Endothelial Cells
Neoplasm Metastasis
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Mir-126 is a conserved modulator of lymphatic development. / Kontarakis, Zacharias; Rossi, Andrea; Ramas, Sophie; Dellinger, Michael T.; Stainier, Didier Y.R.

In: Developmental Biology, 01.01.2018.

Research output: Contribution to journalArticle

Kontarakis, Zacharias ; Rossi, Andrea ; Ramas, Sophie ; Dellinger, Michael T. ; Stainier, Didier Y.R. / Mir-126 is a conserved modulator of lymphatic development. In: Developmental Biology. 2018.
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