Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction.
Alk3 mediated Bmp signaling controls the contribution of epicardially derived cells to the tissues of the atrioventricular junction.
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DOI：
10.1016/j.ydbio.2014.09.031
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发表时间：
2014-12-01
影响因子：
2.7
通讯作者：
Wessels, Andy
中科院分区：
文献类型：
--
作者：
Lockhart, Marie M.;Boukens, Bastiaan J. D.;Phelps, Aimee L.;Brown, Christina-Lin M.;Toomer, Katelynn A.;Burns, Tara A.;Mukherjee, Rupak D.;Norris, Russell A.;Trusk, Thomas C.;van den Hoff, Maurice J. B.;Wessels, Andy
最近使用小鼠模型对心外膜衍生细胞（EPDCs）进行细胞命运追踪的研究表明，在房室（AV）连接处，EPDCs参与房室沟、纤维环和房室瓣壁小叶的间质。然而，对于控制EPDCs对这些组织的贡献的机制却知之甚少。虽然已经证明骨形态发生蛋白（Bmp）信号是AV缓冲层形成所必需的，但其在调节EPDC对AV连接的作用仍未被探索。为了确定Bmp信号在EPDCs对AV连接的作用，使用mWt1/IRES/GFP-Cre （Wt1Cre）小鼠，在心外膜和EPDCs中有条件地删除Bmp受体激活素样激酶3 （Alk3；或Bmpr1a）。胚胎Wt1Cre;Alk3fl/fl标本显示明显较小的房室沟和严重不发达的纤维环。成人Wt1Cre的电生理分析出乎意料的是，Alk3fl/fl小鼠没有心室预兴奋。细胞命运追踪显示房室瓣壁小叶内epdc数量明显减少。产后Wt1Cre;Alk3fl/fl标本显示二尖瓣小叶粘液瘤样改变。总之，这些观察结果表明，Alk3介导的Bmp信号在调节EPDCs对房室沟、纤维环和房室瓣壁小叶的贡献的级联事件中是重要的。此外，本研究表明EPDCs不仅在房室连接处的早期发育事件中起关键作用，而且在房室瓣的正常成熟中也很重要。
Recent studies using mouse models for cell fate tracing of epicardial derived cells (EPDCs) have demonstrated that at the atrioventricular (AV) junction EPDCs contribute to the mesenchyme of the AV sulcus, the annulus fibrosus, and the parietal leaflets of the AV valves. There is little insight, however, into the mechanisms that govern the contribution of EPDCs to these tissues. While it has been demonstrated that bone morphogenetic protein (Bmp) signaling is required for AV cushion formation, its role in regulating EPDC contribution to the AV junction remains unexplored. To determine the role of Bmp signaling in the contribution of EPDCs to the AV junction, the Bmp receptor activin-like kinase 3 (Alk3; or Bmpr1a) was conditionally deleted in the epicardium and EPDCs using the mWt1/IRES/GFP-Cre (Wt1Cre) mouse. Embryonic Wt1Cre;Alk3fl/fl specimens showed a significantly smaller AV sulcus and a severely underdeveloped annulus fibrosus. Electrophysiological analysis of adult Wt1Cre;Alk3fl/fl mice showed, unexpectedly, no ventricular pre-excitation. Cell fate tracing revealed a significant decrease in the number of EPDCs within the parietal leaflets of the AV valves. Postnatal Wt1Cre;Alk3fl/fl specimens showed myxomatous changes in the leaflets of the mitral valve. Together these observations indicate that Alk3 mediated Bmp signaling is important in the cascade of events that regulate the contribution of EPDCs to the AV sulcus, annulus fibrosus, and the parietal leaflets of the AV valves. Furthermore, this study shows that EPDCs do not only play a critical role in early developmental events at the AV junction, but that they also are important in the normal maturation of the AV valves.
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影响因子：
15.9
作者：
Aanhaanen, Wim T. J.;Boukens, Bastiaan J. D.;Christoffels, Vincent M.
通讯作者：
Christoffels, Vincent M.
影响因子：
--
作者：
MARKWALD, RR;FITZHARRIS, TP;MANASEK, FJ
通讯作者：
MANASEK, FJ
影响因子：
3.7
作者：
Jensen B;Boukens BJ;Postma AV;Gunst QD;van den Hoff MJ;Moorman AF;Wang T;Christoffels VM
通讯作者：
Christoffels VM
影响因子：
20.1
作者：
Briggs, Laura E.;Phelps, Aimee L.;Wessels, Andy
通讯作者：
Wessels, Andy
影响因子：
37.8
作者：
LEPESCHKIN, E;SURAWICZ, B
通讯作者：
SURAWICZ, B