MicroRNA-mediated control of developmental lymphangiogenesis
MicroRNA-mediated control of developmental lymphangiogenesis
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DOI：
10.7554/elife.46007
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发表时间：
2019-09-03
期刊：
影响因子：
7.7
通讯作者：
Weinstein, Brant M.
中科院分区：
文献类型：
--
作者：
Jung, Hyun Min;Hu, Ciara T.;Weinstein, Brant M.
对淋巴管生成和淋巴网络组装的分子调控的转录后机制尚不清楚。microRNA是发育过程中重要的转录后调节因子。在这里，我们使用高通量小RNA测序来鉴定miR-204，这是一种高度保守的microRNA，在人类和斑马鱼的淋巴内皮细胞与血液内皮细胞中显著富集。抑制miR-204导致淋巴管损失，而miR-204的内皮过度产生加速淋巴管形成，表明这种microRNA在发育淋巴管生成过程中具有关键的积极作用。我们还确定了NFATC 1转录因子作为人类和斑马鱼中关键的miR-204靶标，并表明NFATC 1抑制导致淋巴增生。由miR-204缺陷引起的内皮细胞功能丧失可以通过miR-204的内皮自主表达或通过抑制NFATC 1而在很大程度上得到挽救。总之，我们的结果突出了适当的淋巴发育所需的miR-204/NFATC 1分子调控轴。
The post-transcriptional mechanisms contributing to molecular regulation of developmental lymphangiogenesis and lymphatic network assembly are not well understood. MicroRNAs are important post-transcriptional regulators during development. Here, we use high throughput small RNA sequencing to identify miR-204, a highly conserved microRNA dramatically enriched in lymphatic vs. blood endothelial cells in human and zebrafish. Suppressing miR-204 leads to loss of lymphatic vessels while endothelial overproduction of miR-204 accelerates lymphatic vessel formation, suggesting a critical positive role for this microRNA during developmental lymphangiogenesis. We also identify the NFATC1 transcription factor as a key miR-204 target in human and zebrafish, and show that NFATC1 suppression leads to lymphatic hyperplasia. The loss of lymphatics caused by miR-204 deficiency can be largely rescued by either endothelial autonomous expression of miR-204 or by suppression of NFATC1. Together, our results highlight a miR-204/NFATC1 molecular regulatory axis required for proper lymphatic development.