title: miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.
abstract: miRNA biogenesis enzyme Drosha cleaves double-stranded primary miRNA by interacting with double-stranded RNA binding protein DGCR8 and processes primary miRNA into precursor miRNA to participate in the miRNA biogenesis pathway. The role of Drosha in vascular smooth muscle cells (VSMCs) has not been well addressed. We generated Drosha conditional knockout (cKO) mice by crossing VSMC-specific Cre mice, SM22-Cre, with Drosha (loxp/loxp) mice. Disruption of Drosha in VSMCs resulted in embryonic lethality at E14.5 with severe liver hemorrhage in mutant embryos. No obvious developmental delay was observed in Drosha cKO embryos. The vascular structure was absent in the yolk sac of Drosha homozygotes at E14.5. Loss of Drosha reduced VSMC proliferation in vitro and in vivo. The VSMC differentiation marker genes, including αSMA, SM22, and CNN1, and endothelial cell marker CD31 were significantly downregulated in Drosha cKO mice compared to controls. ERK1/2 mitogen-activated protein kinase and the phosphatidylinositol 3-kinase/AKT were attenuated in VSMCs in vitro and in vivo. Disruption of Drosha in VSMCs of mice leads to the dysregulation of miRNA expression. Using bioinformatics approach, the interactions between dysregulated miRNAs and their target genes were analyzed. Our data demonstrated that Drosha is required for VSMC survival by targeting multiple signaling pathways.
authors: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors: Pei
authors: P
authors: Fan
authors: Zixuan
authors: Z
authors: Chen
authors: Peng
authors: P
authors: Tian
authors: Wen
authors: W
authors: Liu
authors: Yan
authors: Y
authors: Jiao
authors: Yi
authors: Y
authors: Xue
authors: Anindya
authors: A
authors: Bhattacharya
authors: Jianmin
authors: J
authors: Wu
authors: Meifen
authors: M
authors: Lu
authors: Yuqi
authors: Y
authors: Guo
authors: Yan
authors: Y
authors: Cui
authors: Weikuan
authors: W
authors: Gu
authors: Weiwang
authors: W
authors: Gu
authors: Junming
authors: J
authors: Yue
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D015017:Yolk Sac / Q000098:blood supply
chemical_list: C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C513400:Drosha protein, mouse; D043244:Ribonuclease III
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