The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior.
The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior.
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DOI：
10.1016/j.ydbio.2011.08.008
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发表时间：
2011-10-15
影响因子：
2.7
通讯作者：
Barnett JV
中科院分区：
文献类型：
--
作者：
Sánchez NS;Hill CR;Love JD;Soslow JH;Craig E;Austin AF;Brown CB;Czirok A;Camenisch TD;Barnett JV
心外膜是冠状血管形成所需细胞的主要来源。缺乏编码III型转化生长因子β受体（TGFβR3）基因的两个拷贝的小鼠不能形成冠状血管，但TGFβR3信号冠状血管形成的分子机制尚不清楚。我们使用完整胚胎和E11.5小鼠胚胎的心外膜细胞来揭示TGFβR3信号传导和调节心外膜细胞行为的机制。E13.5胚胎的分析揭示了Tgfbr 3 −/−心脏中心外膜细胞增殖率较低，心外膜来源的细胞侵袭减少。Tgfbr 3 −/−心外膜细胞在体外对TGFβ1和TGFβ2的反应显示增殖减少和侵袭减少。出乎意料的是，TGFβR3的缺失也降低了对心外膜细胞行为的另外两种重要调节因子FGF 2和HMW-HA的反应性。在Tgfbr 3 −/−细胞中恢复全长TGFβR3在体外响应TGFβ1和TGFβ2以及FGF 2和HMW-HA的侵袭中挽救了缺陷。缺失与支架蛋白GIPC 1相互作用所需的3个C末端氨基酸的TGFβR3的表达不能挽救任何缺陷。在Tgfbr 3 −/−细胞中单独过表达GIPC 1不能挽救侵袭，而在Tgfbr 3 +/+细胞中敲低GIPC 1则降低了对TGFβ2、FGF 2和HMW-HA的侵袭反应。我们得出结论，TGFβR3与GIPC 1的相互作用对于调节心外膜细胞的侵袭和生长因子反应性至关重要，心外膜细胞增殖和侵袭的失调导致Tgfbr 3 −/−小鼠冠状血管发育失败。
The epicardium is a major contributor of the cells that are required for the formation of coronary vessels. Mice lacking both copies of the gene encoding the Type III Transforming Growth Factor β Receptor (TGFβR3) fail to form the coronary vasculature, but the molecular mechanism by which TGFβR3 signals coronary vessel formation is unknown. We used intact embryos and epicardial cells from E11.5 mouse embryos to reveal the mechanisms by which TGFβR3 signals and regulates epicardial cell behavior. Analysis of E13.5 embryos reveals a lower rate of epicardial cell proliferation and decreased epicardially-derived cell invasion in Tgfbr3−/− hearts. Tgfbr3−/− epicardial cells in vitro show decreased proliferation and decreased invasion in response to TGFβ1 and TGFβ2. Unexpectedly, loss of TGFβR3 also decreases responsiveness to two other important regulators of epicardial cell behavior, FGF2 and HMW-HA. Restoring full length TGFβR3 in Tgfbr3−/− cells rescued deficits in invasion in vitro in response TGFβ1 and TGFβ2 as well as FGF2 and HMW-HA. Expression of TGFβR3 missing the 3 C-terminal amino acids that are required to interact with the scaffolding protein GIPC1 did not rescue any of the deficits. Overexpression of GIPC1 alone in Tgfbr3−/− cells did not rescue invasion whereas knockdown of GIPC1 in Tgfbr3+/+ cells decreased invasion in response to TGFβ2, FGF2, and HMW-HA. We conclude that TGFβR3 interaction with GIPC1 is critical for regulating invasion and growth factor responsiveness in epicardial cells and that dysregulation of epicardial cell proliferation and invasion contributes to failed coronary vessel development in Tgfbr3−/− mice.
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