WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways.
WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways.
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DOI：
10.1016/j.ydbio.2011.05.668
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发表时间：
2011-08-15
影响因子：
2.7
通讯作者：
Pu WT
中科院分区：
文献类型：
--
作者：
von Gise A;Zhou B;Honor LB;Ma Q;Petryk A;Pu WT
心脏表面有一层上皮膜，即心外膜。在发育中的胚胎中，心外膜表达转录调节因子Wilm肿瘤基因1(Wt1)。通过不完全了解的机制，Wt1失活使正常的心脏发育脱轨。我们研究了Wt1调节心脏发育和心外膜上皮向间充质转化(EMT)的机制。我们使用遗传谱系追踪方法来追踪和分离缺乏Wt1(Wt1KO)的心脏的心外膜和心外膜衍生物。Wt1KO心脏致密心肌细胞增殖减少，冠脉丛形成受损。Wt1KO心外膜未行EMT。Wt1KO心外膜表达减少的LEF1和CTNNB1(β-连环蛋白)，这是典型的WNT/β-连环蛋白信号通路的关键成分。Wt1KO心外膜表达典型的Wnt下游靶基因Axin2、Cyclin D1和Cyclin D2的水平降低，并显示Batga Wnt/b-catenin报告基因活性降低，提示典型的Wnt信号减弱。心外膜受限的CTNNB1功能丧失的心脏类似于Wt1KO心脏，也未能接受心外膜EMT。然而，CTNNB1失活并没有改变WT1的表达，将Wt1定位在规范的Wnt/β-catenin信号的上游。在Wt1KO心外膜中，Wnt5A和Raldh2的表达也显著下调。缺乏Wnt5a或Raldh2的心脏与Wt1KO有共同的表型特征。虽然Wt1已经被提出通过抑制E-钙粘蛋白来调节EMT，但我们在Wt1KO心外膜上没有发现E-钙粘素的变化。总之，我们的研究表明，Wt1通过典型的Wnt、非典型的Wnt和维甲酸信号通路来调节心外膜EMT和心脏发育。
An epithelial sheet, the epicardium, lines the surface of the heart. In the developing embryo, the epicardium expresses the transcriptional regulator Wilm’s Tumor Gene 1 (Wt1). Through incompletely understood mechanisms, Wt1 inactivation derails normal heart development. We investigated mechanisms by which Wt1 regulates heart development and epicardial epithelial to mesenchymal transition (EMT). We used genetic lineage tracing approaches to track and isolate epicardium and epicardium derivatives in hearts lacking Wt1 (Wt1KO). Wt1KO hearts had diminished proliferation of compact myocardium and impaired coronary plexus formation. Wt1KO epicardium failed to undergo EMT. Wt1KO epicardium expressed reduced Lef1 and Ctnnb1 (β-catenin), key components of the canonical Wnt/β-catenin signaling pathway. Wt1KO epicardium expressed decreased levels of canonical Wnt downstream targets Axin2, Cyclin D1, and Cyclin D2 and exhibited decreased activity of the Batgal Wnt/b-catenin reporter transgene, suggestive of diminished canonical Wnt signaling. Hearts with epicardium-restricted Ctnnb1 loss of function resembled Wt1KO hearts and also failed to undergo epicardial EMT. However, Ctnnb1 inactivation did not alter WT1 expression, positioning Wt1 upstream of canonical Wnt/β-catenin signaling. Wnt5a, a prototypic non-canonical Wnt with enriched epicardial expression, and Raldh2, a key regulator of retinoic acid signaling confined to the epicardium, were also markedly downregulated in Wt1KO epicardium. Hearts lacking Wnt5a or Raldh2 shared phenotypic features with Wt1KO. Although Wt1 has been proposed to regulate EMT by repressing E-cadherin, we detected no change in E-cadherin in Wt1KO epicardium. Collectively, our study shows that Wt1 regulates epicardial EMT and heart development through canonical Wnt, non-canonical Wnt, and retinoic acid signaling pathways.
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影响因子：
20.1
作者：
Norden J;Grieskamp T;Lausch E;van Wijk B;van den Hoff MJ;Englert C;Petry M;Mommersteeg MT;Christoffels VM;Niederreither K;Kispert A
通讯作者：
Kispert A
影响因子：
64.5
作者：
KREIDBERG, JA;SARIOLA, H;JAENISCH, R
通讯作者：
JAENISCH, R
影响因子：
4.6
作者：
Hochgreb, T;Linhares, VL;Xavier-Neto, J
通讯作者：
Xavier-Neto, J
影响因子：
2.6
作者：
Moore, AW;Schedl, A;Hastie, ND
通讯作者：
Hastie, ND
影响因子：
11.8
作者：
Tian, Ying;Yuan, Lijun;Morrisey, Edward E.
通讯作者：
Morrisey, Edward E.