Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice.
Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice.
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DOI：
10.1016/j.ydbio.2016.02.033
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发表时间：
2016-04-15
影响因子：
2.7
通讯作者：
Simon AM
中科院分区：
文献类型：
--
作者：
Munger SJ;Geng X;Srinivasan RS;Witte MH;Paul DL;Simon AM
静脉瓣 (VV) 对于从浅静脉和深静脉流向心脏的单向血流至关重要。在某些情况下，先天性瓣膜发育不全或发育不全可能是血管疾病的直接原因，促使人们了解 VV 发育和维持的分子机制。三种间隙连接蛋白（Connexins）Cx37、Cx43 和 Cx47 以高度极化的方式在 VV 上特异性表达。缺乏 Cx37 的成年小鼠不存在 VV；然而，尚不清楚 Cx37 是否是阀门初始形成所必需的。此外，Cx43和Cx47对VV开发的要求尚未研究。在这里，我们提供了小鼠静脉发育过程中 Cx37、Cx43 和 Cx47 表达的详细描述，并通过基因敲除表明每个 Cx 对于正常瓣膜发育是必需的。然而，敲除系中的瓣膜表型表现出 Cx 特异性差异，包括外周或中枢 VV 是否受到基因失活的影响。此外，我们发现 Cx47 无效突变会损害外周 VV 发育，但不影响淋巴瓣形成，这一发现对于理解某些 CX47 突变如何导致人类遗传性淋巴水肿具有重要意义。最后，我们证明了 Foxc2 和 NFATc1 转录因子表达分别在发育的 VV 小叶的下游和上游面之间存在显着的分离，并表明这种分离与 Cx37、Cx43 和 Cx47 的高度极化表达密切相关。 Foxc2 和 NFATc1 在 VV 小叶上表达的分离使得这些因子不太可能在 VV 发育的小叶伸长阶段直接合作。
Venous valves (VVs) are critical for unidirectional blood flow from superficial and deep veins towards the heart. Congenital valve aplasia or agenesis may, in some cases, be a direct cause of vascular disease, motivating an understanding of the molecular mechanisms underlying the development and maintenance of VVs. Three gap junction proteins (Connexins), Cx37, Cx43, and Cx47, are specifically expressed at VVs in a highly polarized fashion. VVs are absent from adult mice lacking Cx37; however it is not known if Cx37 is required for the initial formation of valves. In addition, the requirement of Cx43 and Cx47 for VV development has not been studied. Here, we provide a detailed description of Cx37, Cx43, and Cx47 expression during mouse vein development and show by gene knockout that each Cx is necessary for normal valve development. The valve phenotypes in the knockout lines exhibit Cx-specific differences, however, including whether peripheral or central VVs are affected by gene inactivation. In addition, we show that a Cx47 null mutation impairs peripheral VV development but does not affect lymphatic valve formation, a finding of significance for understanding how some CX47 mutations cause inherited lymphedema in humans. Finally, we demonstrate a striking segregation of Foxc2 and NFATc1 transcription factor expression between the downstream and upstream faces, respectively, of developing VV leaflets and show that this segregation is closely associated with the highly polarized expression of Cx37, Cx43, and Cx47. The partition of Foxc2 and NFATc1 expression at VV leaflets makes it unlikely that these factors directly cooperate during the leaflet elongation stage of VV development.