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 1

Cardiovascular defects in Notch second heart field mutants.

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Cardiovascular defects in Notch second heart field mutants. E17.5–P0 con...
E17.5–P0 control (A), Islet1Cre/+;DNMAML (B and C), and Mef2c-AHF-Cre;DNMAML (D–F) mutants. (A) Arrows indicate pulmonary artery and aorta. (B) A single OFT vessel (arrow) and retroesophageal right subclavian artery. (C) Double outlet right ventricle (arrows) with a right aortic arch and left ductus arteriosus producing a vascular ring. (D) Cervical right aortic arch (arrow). (E) Interruption of the aortic arch, type B (IAA-B, arrow), and retroesophageal right subclavian artery. (F) Double aortic arch (arrows). (G–P) H&E sections of E17.5–E18.5 hearts. (G) Control with separate aorta and pulmonary artery. (H) Islet1Cre/+;DNMAML mutant with single OFT arising from right ventricle. (I) Islet1Cre/+;DNMAML mutant with retroesophageal right subclavian artery dorsal to the trachea. (J and K) Sections from a Mef2c-AHF-Cre+;DNMAML mutant showing a vascular ring. A right-sided circumflex arch (J) runs posterior to the trachea and esophagus en route to a left-sided descending aorta and left ductus arteriosus (K). (L) Control with normal tricuspid valve (arrow). (M and N) Islet1Cre/+;DNMAML with tricuspid atresia (arrow, M), right ventricular hypoplasia, and atrial septal defect (arrow in N). (O and P) Islet1Cre/+;DNMAML (O) and Mef2c-AHF-Cre+;DNMAML (P) hearts showed ventricular septal defects (arrows). ao, aorta; da, ductus arteriosus; e, esophagus; IAA-B, interruption of the aortic arch, type B; la, left atrium; lca, left carotid artery; lsa, left subclavian artery; lv, left ventricle; pa, pulmonary artery; pv, pulmonic valve; ra, right atrium; rca, right carotid artery; rersa, retroesophageal right subclavian artery; rsa, right subclavian artery; rv, right ventricle; ta, truncus arteriosus; tr, trachea; tv, tricuspid valve. Original magnification: ×30 (A–F). Scale bars: 250 μm (G–K), 500 μm (L–P).