Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling.
Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling.
复制标题
在小鼠中结合FOXC2和Connexin37缺失会导致淋巴血管生长和重塑的严重缺陷。
DOI：
10.1016/j.ydbio.2015.06.004
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发表时间：
2015-09-01
影响因子：
2.7
通讯作者：
Simon AM
中科院分区：
文献类型：
--
作者：
Kanady JD;Munger SJ;Witte MH;Simon AM
连接蛋白 (Cxs) 是对脊椎动物细胞间通讯至关重要的蛋白质，最近被证明在淋巴管发育中发挥着关键作用。然而，目前我们对 Cxs 与其他蛋白质和信号通路的功能关系的了解有限。细胞培养研究表明，Cx37 对于协调激活转录因子 NFATc1 是必需的，该转录因子 NFATc1 在淋巴管内皮发育过程中与 Foxc2（另一种转录因子）合作。这些数据表明 Cxs、Foxc2 和 NFATc1 是共同发育途径的一部分。在这里，我们提出了 Foxc2 +/-Cx37 −/− 小鼠的详细特征，证明淋巴网络结构和瓣膜形成依赖于 Foxc2 和 Cx37 的同时胚胎表达和功能。 Foxc2 +/-Cx37−/− 小鼠在子宫内患有淋巴水肿，表现出颅面异常，表现出肠道淋巴管严重扩张，表现出异常乳腺发育，缺乏淋巴瓣膜，并且通常在围产期死亡（分别在 Foxc2 +/- 或 Cx37−/− 小鼠中未观察到结果）。我们提供了淋巴血管网络变化的严格定量记录，突出显示了 Foxc2+/- Cx37−/− 小鼠中发生的特定结构变化。这些数据提供了进一步的证据，表明 Foxc2 和 Cx37 是指导淋巴管生成的共同分子途径中的元件。
Connexins (Cxs), proteins that are vital for intercellular communication in vertebrates, have recently been shown to play a critical role in lymphatic development. However, our knowledge is currently limited regarding the functional relationships of Cxs with other proteins and signaling pathways. Cell culture studies have shown that Cx37 is necessary for coordinated activation of the transcription factor NFATc1, which cooperates with Foxc2 (another transcription factor) during lymphatic endothelial development. These data suggest that Cxs, Foxc2, and NFATc1 are part of a common developmental pathway. Here, we present a detailed characterization of Foxc2 +/−Cx37 −/− mice, demonstrating that lymphatic network architecture and valve formation rely on the concurrent embryonic expression and function of Foxc2 and Cx37. Foxc2 +/−Cx37−/− mice have lymphedema in utero, exhibit craniofacial abnormalities, show severe dilation of intestinal lymphatics, display abnormal lacteal development, lack lymphatic valves, and typically die perinatally (outcomes not seen in Foxc2 +/− or Cx37−/− mice separately). We provide a rigorous, quantitative documentation of lymphatic vascular network changes that highlight the specific structural alterations that occur in Foxc2+/− Cx37−/− mice. These data provide further evidence suggesting that Foxc2 and Cx37 are elements in a common molecular pathway directing lymphangiogenesis.