Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation
Alice Plein, Amélie Calmont, Alessandro Fantin, Laura Denti, Naomi A. Anderson, Peter J. Scambler, Christiana Ruhrberg
Alice Plein, Amélie Calmont, Alessandro Fantin, Laura Denti, Naomi A. Anderson, Peter J. Scambler, Christiana Ruhrberg
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Research Article Vascular biology

Neural crest–derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation

Abstract

In mammals, the outflow tract (OFT) of the developing heart septates into the base of the pulmonary artery and aorta to guide deoxygenated right ventricular blood into the lungs and oxygenated left ventricular blood into the systemic circulation. Accordingly, defective OFT septation is a life-threatening condition that can occur in both syndromic and nonsyndromic congenital heart disease. Even though studies of genetic mouse models have previously revealed a requirement for VEGF-A, the class 3 semaphorin SEMA3C, and their shared receptor neuropilin 1 (NRP1) in OFT development, the precise mechanism by which these proteins orchestrate OFT septation is not yet understood. Here, we have analyzed a complementary set of ligand-specific and tissue-specific mouse mutants to show that neural crest–derived SEMA3C activates NRP1 in the OFT endothelium. Explant assays combined with gene-expression studies and lineage tracing further demonstrated that this signaling pathway promotes an endothelial-to-mesenchymal transition that supplies cells to the endocardial cushions and repositions cardiac neural crest cells (NCCs) within the OFT, 2 processes that are essential for septal bridge formation. These findings elucidate a mechanism by which NCCs cooperate with endothelial cells in the developing OFT to enable the postnatal separation of the pulmonary and systemic circulation.

Authors

Alice Plein, Amélie Calmont, Alessandro Fantin, Laura Denti, Naomi A. Anderson, Peter J. Scambler, Christiana Ruhrberg

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Figure 6

Cardiac NCC–derived SEMA3C signals through NRP1 to promote OFT septation.

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Cardiac NCC–derived SEMA3C signals through NRP1 to promote OFT septation...
(A and B) Serial sections through Wnt1-Cre Sema3cfl/fl and Sema3cfl/fl control (n = 20 each). E12.5 OFTs were immunolabeled for PECAM and SMA and imaged at corresponding proximal, medial, and distal levels. The area indicated with a square bracket in A is shown in higher magnification as single SMA channel in B. Solid arrowheads indicate endothelium of the aorta and pulmonary artery; the solid arrow indicates septal bridge myocardialization; and open arrows indicate absence of septal bridge formation. Wavy arrows highlight the migrating SMA-positive cells, and the angles indicate stalled SMA-positive cells. The dotted lines indicate the axis of septal bridge formation, and the open arrowheads indicate an atypical association between the endocardium and the myocardium. Scale bar: 200 μm (A).