miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.
miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival.
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miRNA生物发生酶Drosha是血管平滑肌细胞存活所必需的。
DOI：
10.1371/journal.pone.0060888
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yue J
中科院分区：
文献类型：
--
作者：
Fan P;Chen Z;Tian P;Liu W;Jiao Y;Xue Y;Bhattacharya A;Wu J;Lu M;Guo Y;Cui Y;Gu W;Gu W;Yue J
miRNA生物合成酶Drosha通过与双链RNA结合蛋白DGCR 8相互作用切割双链初级miRNA，并将初级miRNA加工成前体miRNA以参与miRNA生物合成途径。Drosha在血管平滑肌细胞（VSMC）中的作用尚未得到很好的解决。我们通过将VSMC特异性Cre小鼠SM 22-Cre与Drosha loxp/loxp小鼠杂交来产生Drosha条件性敲除（cKO）小鼠。VSMC中Drosha的破坏导致E14.5的胚胎死亡，突变胚胎中出现严重的肝出血。在Drosha cKO胚胎中未观察到明显的发育延迟。在E14.5，Drosha纯合子的卵黄囊中没有血管结构。Drosha的缺失降低了体外和体内VSMC的增殖。与对照组相比，Drosha cKO小鼠的VSMC分化标志物基因（包括αSMA、SM 22和CNN 1）和内皮细胞标志物CD 31显著下调。ERK 1/2丝裂原活化蛋白激酶和磷脂酰肌醇3-激酶/AKT在体外和体内VSMCs中减弱。Drosha在小鼠VSMCs中的破坏导致miRNA表达失调。利用生物信息学方法分析了miRNAs与靶基因的相互作用。我们的数据表明，Drosha是VSMC生存所必需的靶向多个信号通路。
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.
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影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
影响因子：
64.8
作者：
Cordes KR;Sheehy NT;White MP;Berry EC;Morton SU;Muth AN;Lee TH;Miano JM;Ivey KN;Srivastava D
通讯作者：
Srivastava D
影响因子：
64.8
作者：
Chendrimada, TP;Gregory, RI;Shiekhattar, R
通讯作者：
Shiekhattar, R
影响因子：
4.8
作者：
Chen, Zixuan;Wu, Jianmin;Yue, Junming
通讯作者：
Yue, Junming
影响因子：
9.2
作者：
Landthaler, M;Yalcin, A;Tuschl, T
通讯作者：
Tuschl, T