Cellular communication across tissues is an essential process during embryonic development. Secreted factors with potent morphogenetic activity are key elements of this cross-talk, and precise regulation of their expression is required to elicit appropriate physiological responses. MicroRNAs (miRNAs) are versatile post-transcriptional modulators of gene expression. However, the large number of putative targets for each miRNA hinders the identification of physiologically relevant miRNA-target interactions. Here we show that miR-1 and miR-206 negatively regulate angiogenesis during zebrafish development. Using target protectors, our results indicate that miR-1/206 directly regulate the levels of Vascular endothelial growth factor A (VegfA) in muscle, controlling the strength of angiogenic signaling to the endothelium. Conversely, reducing the levels of VegfAa, but not VegfAb, rescued the increase in angiogenesis observed when miR-1/206 were knocked down. These findings uncover a novel function for miR-1/206 in the control of developmental angiogenesis through the regulation of VegfA, and identify a key role for miRNAs as regulators of cross-tissue signaling.
Funding
This work was supported by the Pew Scholars Program in the Biomedical Sciences, the Yale Scholar Program, the Muscular Dystrophy Association and National Institutes of Health (NIH) grants [R01GM081602-05] to A.J.G.; by a Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowship for Research Abroad and Grants in Aid for Young Scientist to Y.M.; The Uehara Memorial Foundation and The NOVARTIS Foundation (Japan) for the Promotion of Science [Y.M.]; and a Scientist Development Grant-American Heart Association [0835481N] and NIH grant [R01HL105945] from the National Heart, Lung, and Blood Institute (NHLBI) to Y.S. Deposited in PMC for release after 12 months.
