Abstract 633: Semaphorin3e-Plexind1 Signaling is Required for Cardiac Ventricular Compaction

Abstract

Left ventricular noncompaction (LVNC) is one of the most common forms of genetic cardiomyopathy characterized by excessive trabeculation and impaired myocardial compaction during fetal development. LVNC patients are at higher risk to develop left or right ventricular failure, or both. While key regulators for cardiac chamber development are well studied, the role of Semaphorin-Plexin signaling in this process remains poorly understood. Here, we demonstrate that genetic deletion of Plxnd1, a class 3 semaphorin receptor in endothelial cells, leads to severe cardiac chamber defects, as characterized by excessive trabeculation and non-compaction similar to LVNC patients. Loss of Plxnd1 results in decreased expression of extracellular matrix (ECM) proteolytic genes leading to excessive deposition of cardiac jelly. We demonstrate that Plxnd1 deficiency is associated with an increase in the expression of Notch and its downstream target genes. In addition, inhibition of Notch signaling pathway can partially rescue the excessive trabeculation and non-compaction phenotype present in Plxnd1 mutants. Furthermore, we demonstrate that Semaphorin 3e (Sema3e), one of Plxnd1’s ligands is expressed in the developing heart and is required for myocardial compaction. Collectively, our results demonstrate that the Sema3e-Plxnd1 pathway is essential for myocardial trabeculation and compaction.