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 8

SEMA3C signals through NRP1 to promote convergence of cardiac NCCs and septal bridge myocardialization.

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SEMA3C signals through NRP1 to promote convergence of cardiac NCCs and s...
E12.5 OFT sections of the indicated genotypes were immunolabeled for PLXNA2 and SMA (A) or YFP and the early SMC and myocyte marker SM22α (B). Arrows indicate NCCs in the septal bridge in WTs (n = 6) and mice lacking VEGF-A or SEMA3C signaling through NRPs (n = 3 each). Curved arrows highlight SMA-positive cells migrating toward centrally located NCCs, and wavy arrows indicate SMA-positive cells migrating toward abnormal lateral NCCs in A. Double arrowheads denote the abnormal lateral position of NCCs in the other genotypes, while the open arrow in B indicates a smaller population of neural crest–derived cells that do not express PLXNA2, as shown in A, which still migrate toward the central OFT, but are not sufficient to induce proximal OFT septation. Mean ± SD, 2-tailed, unpaired Student’s t test. Scale bars: 100 μm.