Sox18 induces development of the lymphatic vasculature in mice
Sox18 induces development of the lymphatic vasculature in mice
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DOI：
10.1038/nature07391
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发表时间：
2008-12-04
期刊：
影响因子：
64.8
通讯作者：
Koopman, Peter
中科院分区：
文献类型：
--
作者：
Francois, Mathias;Caprini, Andrea;Koopman, Peter
淋巴系统在组织液调节和肿瘤转移中起关键作用，淋巴缺陷是许多病理状态的基础，包括淋巴水肿、淋巴管扩张、淋巴管瘤和淋巴发育不良（1-3）。然而，胚胎中淋巴系统的起源以及指导淋巴管网络生长的机制仍然不清楚。淋巴管被认为是在淋巴标志基因Prox 1的影响下从主静脉出芽的内皮前体细胞产生的（Proxo同源框1;参考文献4）。转录因子基因SOX 18（SRY（性别决定区Y）盒18）的缺陷导致人类淋巴功能减退-淋巴水肿-毛细血管扩张综合征中的淋巴功能障碍（5），表明Sox 18也可能在淋巴发育或功能中发挥作用。在这里，我们使用小鼠的分子，细胞和遗传分析表明，Sox 18作为一个分子开关，以诱导淋巴管内皮细胞的分化。Sox 18在主静脉细胞的亚群中表达，所述亚群随后共表达Prox 1并迁移以形成淋巴管。Sox 18通过与其近端启动子结合直接激活Prox 1的转录。Sox 18在血管内皮细胞中的过表达诱导它们表达Prox 1和其他淋巴管内皮标志物，而Sox 18缺失的胚胎显示出对主静脉的淋巴管内皮细胞分化的完全阻断。我们的研究结果表明，Sox 18在发展中的淋巴管生成的关键作用，并提出了新的途径，以调查人类淋巴管病的治疗管理。
The lymphatic system plays a key role in tissue fluid regulation and tumour metastasis, and lymphatic defects underlie many pathological states including lymphoedema, lymphangiectasia, lymphangioma and lymphatic dysplasia(1-3). However, the origins of the lymphatic system in the embryo, and the mechanisms that direct growth of the network of lymphatic vessels, remain unclear. Lymphatic vessels are thought to arise from endothelial precursor cells budding from the cardinal vein under the influence of the lymphatic hallmark gene Prox1 ( prospero homeobox 1; ref. 4). Defects in the transcription factor gene SOX18 ( SRY ( sex determining region Y) box 18) cause lymphatic dysfunction in the human syndrome hypotrichosis- lymphoedema- telangiectasia(5), suggesting that Sox18 may also play a role in lymphatic development or function. Here we use molecular, cellular and genetic assays in mice to show that Sox18 acts as a molecular switch to induce differentiation of lymphatic endothelial cells. Sox18 is expressed in a subset of cardinal vein cells that later co- express Prox1 and migrate to form lymphatic vessels. Sox18 directly activates Prox1 transcription by binding to its proximal promoter. Overexpression of Sox18 in blood vascular endothelial cells induces them to express Prox1 and other lymphatic endothelial markers, while Sox18- null embryos show a complete blockade of lymphatic endothelial cell differentiation from the cardinal vein. Our findings demonstrate a critical role for Sox18 in developmental lymphangiogenesis, and suggest new avenues to investigate for therapeutic management of human lymphangiopathies.