NFATc1 regulates lymphatic endothelial development.
NFATc1 regulates lymphatic endothelial development.
复制标题
DOI：
10.1016/j.mod.2009.02.003
复制
发表时间：
2009-05
影响因子：
2.6
通讯作者：
Akeson, Ann L.
中科院分区：
文献类型：
--
作者：
Kulkarni, Rishikesh M.;Greenberg, James M.;Akeson, Ann L.
NFATc 1转录因子在T细胞分化、心脏瓣膜形态发生和破骨细胞发生中对谱系选择至关重要。我们确定了钙调神经磷酸酶-NFAT信号传导在淋巴发育和模式化中的作用。NFATc 1与淋巴标志物Prox-1、VEGFR-3和podoplanin在主静脉上共定位，因为淋巴管内皮细胞（LEC）被指定，并且当它们分离成淋巴囊和成熟淋巴管时。在NFATc 1基因敲除小鼠中，Prox-1、VEGFR-3和podoplanin阳性内皮细胞在E11.5时从主静脉出芽，但很少合并成淋巴囊。NFAT激活需要磷酸酶钙调磷酸酶。在子宫内用钙调神经磷酸酶抑制剂环孢霉素-A处理的胚胎显示出细胞质NFATc 1，减少了podoplanin和FGFR-3的表达，这表明钙调神经磷酸酶-NFAT信号传导在淋巴模式中的作用。在损伤诱导的淋巴管生成的小鼠模型中，NFATc 1在肺特异性VEGF-A过表达诱导的新淋巴管上表达。缺乏钙调磷酸酶Aβ调节亚基的小鼠，核NFAT减少，对VEGF-A的反应不明显，淋巴管生成增加。在体外，内源性和VEGF-A诱导的VEGFR-3和podoplanin表达的人微血管内皮细胞减少了siRNA的NFATc 1，减少的水平与siRNA的Prox-1。在报告基因分析中，NFATc 1激活淋巴特异性基因启动子。这些结果证明了钙调神经磷酸酶-NFAT途径在淋巴管生成中的作用，并表明NFATc 1是参与的主要NFAT。
NFATc1 transcription factor is critical for lineage selection in T-cell differentiation, cardiac valve morphogenesis and osteoclastogenesis. We identified a role for calcineurin-NFAT signaling in lymphatic development and patterning. NFATc1 was colocalized with lymphatic markers Prox-1, VEGFR-3 and podoplanin on cardinal vein as lymphatic endothelial cells (LEC) are specified and as they segregate into lymph sacs and mature lymphatics. In NFATc1 null mice, Prox-1, VEGFR-3 and podoplanin positive endothelial cells sprouted from the cardinal vein at E11.5, but poorly coalesced into lymph sacs. NFAT activation requires the phosphatase calcineurin. Embryos treated in utero with the calcineurin inhibitor cyclosporine-A showed cytoplasmic NFATc1, diminished podoplanin and FGFR-3 expression by the lymphatics and irregular patterning of the LEC sprouts coming off the jugular lymph sac, which suggests a role for calcineurin-NFAT signaling in lymphatic patterning. In a murine model of injury-induced lymphangiogenesis, NFATc1 was expressed on the neolymphatics induced by lung-specific overexpression of VEGF-A. Mice lacking the calcineurin Aβ regulatory subunit, with diminished nuclear NFAT, failed to respond to VEGF-A with increased lymphangiogenesis. In vitro, endogenous and VEGF-A-induced VEGFR-3 and podoplanin expression by human microvascular endothelial cells was reduced by siRNA to NFATc1, to levels comparable to reductions seen with siRNA to Prox-1. In reporter assays, NFATc1 activated lymphatic specific gene promoters. These results demonstrate the role of calcineurin-NFAT pathway in lymphangiogenesis and suggest that NFATc1 is the principle NFAT involved.
登录
查看更多内容
影响因子：
4.8
作者：
Davé, V;Childs, T;Whitsett, JA
通讯作者：
Whitsett, JA
影响因子：
11.8
作者：
Gale, NW;Thurston, G;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
DOI：
10.1073/pnas.072647999
发表时间：
2002-04-02
影响因子：
11.1
作者：
Bueno, OF;Wilkins, BJ;Molkentin, JD
通讯作者：
Molkentin, JD
DOI：
10.1093/jnci/94.11.819
发表时间：
2002-06-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
He, YL;Kozaki, KI;Alitalo, K
通讯作者：
Alitalo, K
影响因子：
64.5
作者：
Graef, IA;Chen, F;Crabtree, GR
通讯作者：
Crabtree, GR