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

Proceedings of the National Academy of Sciences of the United States of America
Diana N NunesRenata Pasqualini

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.

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Citations

Dec 18, 2019·PLoS Genetics·Rodrigo Guarischi-SousaRicardo J Giordano
Aug 28, 2019·Experimental and Therapeutic Medicine·Huiting ZhouHua Xu
Mar 17, 2020·Clinical & Experimental Ophthalmology·Heeyoon ChoYong U Shin
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Mar 19, 2019·British Journal of Pharmacology·Chiara Bianca Maria PlataniaClaudio Bucolo
Mar 18, 2021·Acta Ophthalmologica·Flavia PlastinoHelder André
Dec 29, 2020·Aging·Catherine MénardPrzemyslaw Sapieha
Jul 29, 2021·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Yan GuoWei-Tao Song

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