Abstract 19694: Etv2-Regulated Micrornas are Essential for Endothelial Development
Precise regulation of the fate of endothelial precursors is critical for vascular development. Currently, no known microRNAs have been shown to have a functional role in the specification of the endothelial progenitor cell fate during early embryogenesis. To decipher the requirement of miRNAs during endothelial and vascular development, we disrupted Dicer in a tissue-specific manner, utilizing the Etv2-Cre transgenic mouse model that we engineered to ablate microRNA biogenesis in endothelial progenitors. Using this strategy, we determined that miRNA biogenesis is essential for vasculogenesis as Etv2-Cre:DicerF/F embryos are lethal by E11.5-12.5. Histological analysis reveals that the Dicer conditional knockout embryos have severe vascular defects and hemorrhage compared to the wildtype littermates. We have previously reported enrichment of a Pdgfr-α+ cell population in the Etv2 mutant embryos, however the mechanism is unclear. In the present study, we have identified miR-27a and miR-130a as Etv2 downstream target genes. Using transcriptional assays, we observed that Etv2 transactivated both miR-27a and miR-130a in a dose-dependent manner. Further, we have identified and mapped the miR-27a and miR130a binding sites on the Pdgfr- α 3’-UTR. Our transcriptional assays indicate that miR-27a and miR-130a attenuate the expression of Pdgfr- α. Collectively, these findings identify novel microRNA-mediated mechanisms that govern lineage decisions of mesodermal progenitors and ultimately impact cardiovascular development.
- © 2012 by American Heart Association, Inc.