Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation
Foxc1 and Foxc2 deletion causes abnormal lymphangiogenesis and correlates with ERK hyperactivation
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DOI：
10.1172/jci80465
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Kume, Tsutomu
中科院分区：
文献类型：
--
作者：
Fatima, Anees;Wang, Ying;Kume, Tsutomu
淋巴管系统对于维持间质液稳态是必不可少的，并且功能失调的淋巴管生成有助于各种病理过程，包括炎性疾病和肿瘤转移。FOXC 2的突变主要与迟发性水肿相关;然而，FOXC 2和一个密切相关的因子FOXC 1在淋巴系统中的确切作用在很大程度上仍然未知。在这里，我们确定了FOXC 1和FOXC 2在淋巴管生长中调节ERK信号的分子级联。在小鼠中，淋巴管内皮细胞特异性（LEC特异性）缺失Foxc 1、Foxc 2或两者导致LEC增殖增加、淋巴管扩大和淋巴管形态发生异常。与对照动物的LEC相比，来自缺乏Foxc 1和Foxc 2的小鼠的LEC表现出Ras调节因子的异常表达，并且具有LEC特异性Foxc 1和Foxc 2缺失的胚胎，单独或组合，表现出ERK过度激活。子宫内的药理学ERK抑制消除了FOXC缺陷胚胎中异常增大的淋巴管。总之，这些结果确定FOXC 1和FOXC 2作为淋巴管生成的重要调节因子，并表明一个新的潜在的机制基础，与肿瘤相关的疾病。
The lymphatic vasculature is essential for maintaining interstitial fluid homeostasis, and dysfunctional lymphangiogenesis contributes to various pathological processes, including inflammatory disease and tumor metastasis. Mutations in FOXC2 are dominantly associated with late-onset lymphedema; however, the precise role of FOXC2 and a closely related factor, FOXC1, in the lymphatic system remains largely unknown. Here we identified a molecular cascade by which FOXC1 and FOXC2 regulate ERK signaling in lymphatic vessel growth. In mice, lymphatic endothelial cell-specific (LEC-specific) deletion of Foxc1, Foxc2, or both resulted in increased LEC proliferation, enlarged lymphatic vessels, and abnormal lymphatic vessel morphogenesis. Compared with LECs from control animals, LECs from mice lacking both Foxc1 and Foxc2 exhibited aberrant expression of Ras regulators, and embryos with LEC-specific deletion of Foxc1 and Foxc2, alone or in combination, exhibited ERK hyperactivation. Pharmacological ERK inhibition in utero abolished the abnormally enlarged lymphatic vessels in FOXC-deficient embryos. Together, these results identify FOXC1 and FOXC2 as essential regulators of lymphangiogenesis and indicate a new potential mechanistic basis for lymphatic-associated diseases.