Endocardial to Myocardial Notch-Wnt-Bmp Axis Regulates Early Heart Valve Development

Yidong Wang, Bingruo Wu, Alyssa A. Chamberlain, Wendy Lui, Pratistha Koirala, Katalin Susztak, Diana Klein, Verdon Taylor, Bin Zhou

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Endocardial to mesenchymal transformation (EMT) is a fundamental cellular process required for heart valve formation. Notch, Wnt and Bmp pathways are known to regulate this process. To further address how these pathways coordinate in the process, we specifically disrupted Notch1 or Jagged1 in the endocardium of mouse embryonic hearts and showed that Jagged1-Notch1 signaling in the endocardium is essential for EMT and early valvular cushion formation. qPCR and RNA in situ hybridization assays reveal that endocardial Jagged1-Notch1 signaling regulates Wnt4 expression in the atrioventricular canal (AVC) endocardium and Bmp2 in the AVC myocardium. Whole embryo cultures treated with Wnt4 or Wnt inhibitory factor 1 (Wif1) show that Bmp2 expression in the AVC myocardium is dependent on Wnt activity; Wnt4 also reinstates Bmp2 expression in the AVC myocardium of endocardial Notch1 null embryos. Furthermore, while both Wnt4 and Bmp2 rescue the defective EMT resulting from Notch inhibition, Wnt4 requires Bmp for its action. These results demonstrate that Jagged1-Notch1 signaling in endocardial cells induces the expression of Wnt4, which subsequently acts as a paracrine factor to upregulate Bmp2 expression in the adjacent AVC myocardium to signal EMT.

Original languageEnglish (US)
Article numbere60244
JournalPloS one
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Wang, Y., Wu, B., Chamberlain, A. A., Lui, W., Koirala, P., Susztak, K., Klein, D., Taylor, V., & Zhou, B. (2013). Endocardial to Myocardial Notch-Wnt-Bmp Axis Regulates Early Heart Valve Development. PloS one, 8(4), [e60244]. https://doi.org/10.1371/journal.pone.0060244