A Notch-Dependent Transcriptional Hierarchy Promotes Mesenchymal Transdifferentiation in the Cardiac Cushion
A Notch-Dependent Transcriptional Hierarchy Promotes Mesenchymal Transdifferentiation in the Cardiac Cushion
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DOI：
10.1002/dvdy.24127
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发表时间：
2014-07-01
影响因子：
2.5
通讯作者：
Karsan, Aly
中科院分区：
文献类型：
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作者：
Chang, Alex C. Y.;Garside, Victoria C.;Karsan, Aly
背景：瓣膜间隔缺损是最常见的先天性心脏病。Notch信号诱导的小鼠胚胎9.5天房室管（AVC）垫中的内皮-间质转化（EMT）是早期瓣膜发育过程中的必需步骤。对EMT期间内皮细胞（EC）中激活的转录网络以及这些途径如何指导瓣膜成熟的见解缺乏。结果：我们发现，在E11.5，AVC-EC保留的能力，进行Notch依赖性EMT时，胶原。在E10.5处的EC-Notch抑制阻断了E11.5 AVC-EC中已知间充质基因的表达。为了了解E9.5之后Notch信号传导下游的遗传网络和AVC发展，我们构建了对应于野生型小鼠和EC-Notch抑制小鼠中E11.5 AVC和心房的不同细胞类型的Tag-Seq文库。我们在AVC-EC中鉴定了1,400个潜在的Notch靶点，其中124个是转录因子（TF）。从124个转录因子中，我们构建了一个转录层次结构，并确定了网络中的10个上游转录因子。结论：我们验证了4个上游TF作为富集AVC-EC的Notch靶标。在功能上，我们显示这4个TF在AVC外植体测定中调节EMT。Notch下游的这些新的信号通路可能与瓣膜发育相关。(C)2014 Wiley Periodicals，Inc.
Background: Valvuloseptal defects are the most common congenital heart defects. Notch signaling-induced endothelial-to-mesenchymal transition (EMT) in the atrioventricular canal (AVC) cushions at murine embryonic day (E) 9.5 is a required step during early valve development. Insights to the transcriptional network that is activated in endocardial cells (EC) during EMT and how these pathways direct valve maturation are lacking. Results: We show that at E11.5, AVC-EC retain the ability to undergo Notch-dependent EMT when explanted on collagen. EC-Notch inhibition at E10.5 blocks expression of known mesenchymal genes in E11.5 AVC-EC. To understand the genetic network and AVC development downstream of Notch signaling beyond E9.5, we constructed Tag-Seq libraries corresponding to different cell types of the E11.5 AVC and atrium in wild-type mice and in EC-Notch inhibited mice. We identified 1,400 potential Notch targets in the AVC-EC, of which 124 are transcription factors (TF). From the 124 TFs, we constructed a transcriptional hierarchy and identify 10 upstream TFs within the network. Conclusions: We validated 4 of the upstream TFs as Notch targets that are enriched in AVC-EC. Functionally, we show these 4 TFs regulate EMT in AVC explant assays. These novel signaling pathways downstream of Notch are potentially relevant to valve development. (C) 2014 Wiley Periodicals, Inc.