MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.
MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.
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DOI：
10.1161/circresaha.110.227926
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发表时间：
2010-11-26
影响因子：
20.1
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Small EM;Sutherland LB;Rajagopalan KN;Wang S;Olson EN
功能性血管系统的建立需要新生血管的相互连接和重塑。对影响内皮细胞(EC)迁移和功能的因素的精确调控对于这些刻板印象的血管构型事件至关重要。分泌的缝隙配体及其Robo受体构成了胚胎发育过程中控制神经元和血管内皮细胞定向迁移的关键信号通路，但其调控机制尚不完全清楚。识别调控Sit-Robo途径和血管模式的microRNAs。在这里，我们提供了由Sit基因内含子编码的microRNA(MiR)-218抑制Robo1和Robo2以及硫酸乙酰肝素(HS)生物合成途径的多种成分的表达的证据。使用体外和体内的方法，我们证明了miR-218直接抑制Robo1，Robo2和葡萄糖醛酸基C5-差向异构酶(GLCE)的表达，并且完整的miR-218-Sit-Robo调控网络对于正常的视网膜血管形成是必不可少的。MiR-218的敲除导致该信号轴的异常调节，EC的异常迁移和视网膜血管系统的复杂性降低。我们的发现将Sit基因的表达与Robo受体和硫酸乙酰肝素生物合成酶的转录后调节联系起来，从而能够精确控制影响发育过程中血管组织的血管引导信号。
Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell (EC) migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular ECs during embryonic development, but the mechanisms of their regulation are incompletely understood. To identify microRNAs regulating aspects of the Slit-Robo pathway and vascular patterning. Here we provide evidence that microRNA (miR) -218, which is encoded by an intron of the Slit genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate (HS) biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5-epimerase (GLCE), and that an intact miR-218–Slit–Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal EC migration and reduced complexity of the retinal vasculature. Our findings link Slit gene expression to the post-transcriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development.