Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.
Elife. 2019 Sep 3;8:e46007. doi: 10.7554/eLife.46007.
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.
尚不清楚有助于发育性淋巴管生成和淋巴管网络组装的分子调控的转录后机制。microRNA 是发育过程中重要的转录后调控因子。在这里，我们使用高通量小 RNA 测序来鉴定 miR-204，这是一种在人类和斑马鱼的淋巴管内皮细胞中高度保守的 microRNA，在血液内皮细胞中显著富集。抑制 miR-204 会导致淋巴管丧失，而内皮细胞中 miR-204 的过表达会加速淋巴管的形成，这表明在发育性淋巴管生成过程中，这种 microRNA 具有关键的积极作用。我们还鉴定了 NFATC1 转录因子作为人类和斑马鱼中 miR-204 的关键靶标，并表明 NFATC1 抑制会导致淋巴管增生。miR-204 缺陷引起的淋巴管缺失可以通过内皮细胞自主表达 miR-204 或抑制 NFATC1 来很大程度上挽救。总之，我们的结果强调了 miR-204/NFATC1 分子调节轴在适当的淋巴管发育中所必需的。
