A Notch-dependent transcriptional hierarchy promotes mesenchymal transdifferentiation in the cardiac cushion

Alex C Y Chang, Victoria C. Garside, Michele Fournier, Justin Smrz, Pavle Vrljicak, Patricia Umlandt, Megan Fuller, Gordon A. Robertson, Yongjun Zhao, Angela Tam, Steven J M Jones, Marco A. Marra, Pamela A. Hoodless, Aly Karsan

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

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. Developmental Dynamics 243:894-905, 2014.

Original languageEnglish
Pages (from-to)894-905
Number of pages12
JournalDevelopmental Dynamics
Volume243
Issue number7
DOIs
Publication statusPublished - Jul 2014
Externally publishedYes

Keywords

  • Cardiac cushion
  • EMT
  • Notch

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