Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development
Frances A. High, … , Warren S. Pear, Jonathan A. Epstein
Frances A. High, … , Warren S. Pear, Jonathan A. Epstein
Published June 8, 2009
Citation Information: J Clin Invest. 2009;119(7):1986-1996. https://doi.org/10.1172/JCI38922.
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Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development

Abstract

Notch signaling is vital for proper cardiovascular development and function in both humans and animal models. Indeed, mutations in either JAGGED or NOTCH cause congenital heart disease in humans and NOTCH mutations are associated with adult valvular disease. Notch typically functions to mediate developmental interactions between adjacent tissues. Here we show that either absence of the Notch ligand Jagged1 or inhibition of Notch signaling in second heart field tissues results in murine aortic arch artery and cardiac anomalies. In mid-gestation, these mutants displayed decreased Fgf8 and Bmp4 expression. Notch inhibition within the second heart field affected the development of neighboring tissues. For example, faulty migration of cardiac neural crest cells and defective endothelial-mesenchymal transition within the outflow tract endocardial cushions were observed. Furthermore, exogenous Fgf8 was sufficient to rescue the defect in endothelial-mesenchymal transition in explant assays of endocardial cushions following Notch inhibition within second heart field derivatives. These data support a model that relates second heart field, neural crest, and endocardial cushion development and suggests that perturbed Notch-Jagged signaling within second heart field progenitors accounts for some forms of congenital and adult cardiac disease.

Authors

Frances A. High, Rajan Jain, Jason Z. Stoller, Nicole B. Antonucci, Min Min Lu, Kathleen M. Loomes, Klaus H. Kaestner, Warren S. Pear, Jonathan A. Epstein

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Figure 3

Jag1 is an essential Notch ligand in the second heart field.

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Jag1 is an essential Notch ligand in the second heart field. (A and...
(A and B) In situ hybridizations for Jag1 in control embryos. (A) Jag1 expression in pharyngeal endoderm (arrows, E10.5 embryo). (B) Jag1 expression in pharyngeal mesenchyme (arrow), OFT (arrowheads), and aortic arch arteries (asterisks, E11.5 embryo). (C and D) Jag1 immunostaining through E11.5 control (C) and mutant (D) embryos demonstrated loss of Jag1 expression in pharyngeal mesenchyme (arrow) and OFT (black arrowheads) of the mutant. Expression was maintained in the aortic arch arteries (white arrowheads). (E–G) Photographs and diagrams of hearts from E18.5 control (E) and mutant (F and G) embryos. (E) Arrows indicate pulmonary artery and aorta. (F) Double outlet right ventricle (arrows). (G) Double outlet right ventricle (arrows) and an interrupted aortic arch. (H–K) H&E-stained sections of E18.5 control (H and J) and mutant (I and K) hearts, demonstrating a double outlet right ventricle and a ventricular septal defect (arrow). (L–O) In situ hybridization of E10.5 control (L and N) and mutant (M and O) embryos. Control sections (L and N) demonstrated normal neural crest expression of Sema3C (L) and PlexinA2 (N) in the 2 clusters of cells in the center of the developing OFT cushions (dotted circles in N), while mutants (M and O) demonstrated reduced expression. Original magnification, ×30 (E–G). Scale bars: 250 μm (A, C, D, H, and I), 500 μm (B, J, and K), 100 μm (L–O).