TY - JOUR
T1 - Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch
AU - Nunes, Diana N.
AU - Dias-Neto, Emmanuel
AU - Cardó-Vila, Marina
AU - Edwards, Julianna K.
AU - Dobroff, Andrey S.
AU - Giordano, Ricardo J.
AU - Mandelin, Jami
AU - Brentani, Helena P.
AU - Hasselgren, Catrin
AU - Yao, Virginia J.
AU - Marchiò, Serena
AU - Pereira, Carlos A.B.
AU - Passetti, Fabio
AU - Calin, George A.
AU - Sidman, Richard L.
AU - Arap, Wadih
AU - Pasqualini, Renata
N1 - Publisher Copyright:
© 2015, National Academy of Sciences. All rights reserved.
PY - 2015/3/24
Y1 - 2015/3/24
N2 - 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.
AB - 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.
KW - Eye
KW - Hypoxia
KW - Mouse neovascularization model
KW - miRNA family
KW - miRNA regulatory network
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U2 - 10.1073/pnas.1500008112
DO - 10.1073/pnas.1500008112
M3 - Article
C2 - 25775553
AN - SCOPUS:84925426226
SN - 0027-8424
VL - 112
SP - 3770
EP - 3775
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -