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.
Highlights
Formation of heart valves is critical for heart function and is required for both embryogenesis and postnatal life
Heart valve development begins with the mesenchymal transformation of endocardial cells (EMT) at embryonic day (E) 9.5 and E10.5 at endocardial cushions of atrioventricular canal (AVC) and outflow tract (OFT)
Using RNA in situ hybridization, we further examined expression of Wnt4 and Bmp2, which are specific for AVC endocardium and myocardium, respectively
Summary
Formation of heart valves is critical for heart function and is required for both embryogenesis and postnatal life Defects in this process may cause congenital heart valve disease [1,2,3]. Studies of EMT have identified Notch, Wnt, and Bmp pathways that act in the endocardium and/or myocardium of cushions to regulate this process. Ablation of endothelial Wnt [13] and myocardial Bmp [14,15] activities inhibit EMT and valve development. Ma and Martin et al have reported that myocardial Bmp is required for endocardial Notch expression [15], and studies by Luna-Zurita and De la Pompa et al have shown that Bmp drives EMT of ventricular endocardial cells which ectopically express active Notch1 [16]. How Notch, Wnt, and Bmp pathways coordinate in EMT process is still incompletely understood
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