Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch

Diana N. Nunes, Emmanuel Dias-Neto, Marina Cardó-Vila, Julianna K. Edwards, Andrey S. Dobroff, Ricardo J. Giordano, Jami Mandelin, Helena P. Brentani, Catrin Hasselgren, Virginia J. Yao, Serena Marchiò, Carlos A.B. Pereira, Fabio Passetti, George A. Calin, Richard L. Sidman, Wadih Arap, Renata Pasqualini

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.

Original languageEnglish (US)
Pages (from-to)3770-3775
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number12
DOIs
StatePublished - Mar 24 2015
Externally publishedYes

Keywords

  • Eye
  • Hypoxia
  • Mouse neovascularization model
  • miRNA family
  • miRNA regulatory network

ASJC Scopus subject areas

  • General

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