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Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction
Reddemma Sandireddy, … , Jonathan A. Epstein, Manvendra K. Singh
Reddemma Sandireddy, … , Jonathan A. Epstein, Manvendra K. Singh
Published August 22, 2019
Citation Information: JCI Insight. 2019;4(16):e125908. https://doi.org/10.1172/jci.insight.125908.
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Research Article Cardiology Development Article has an altmetric score of 51

Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction

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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. Patients with LVNC are at higher risk of developing left/right ventricular failure or both. Although the key regulators for cardiac chamber development are well studied, the role of semaphorin (Sema)/plexin signaling in this process remains poorly understood. In this article, we demonstrate that genetic deletion of Plxnd1, a class-3 Sema receptor in endothelial cells, leads to severe cardiac chamber defects. They were characterized by excessive trabeculation and noncompaction similar to patients with LVNC. Loss of Plxnd1 results in decreased expression of extracellular matrix proteolytic genes, leading to excessive deposition of cardiac jelly. We demonstrate that Plxnd1 deficiency is associated with an increase in Notch1 expression and its downstream target genes. In addition, inhibition of the Notch signaling pathway partially rescues the excessive trabeculation and noncompaction phenotype present in Plxnd1 mutants. Furthermore, we demonstrate that Semaphorin 3E (Sema3E), one of PlexinD1’s known ligands, is expressed in the developing heart and is required for myocardial compaction. Collectively, our study uncovers what we believe to be a previously undescribed role of the Sema3E/PlexinD1 signaling pathway in myocardial trabeculation and the compaction process.

Authors

Reddemma Sandireddy, Dasan Mary Cibi, Priyanka Gupta, Anamika Singh, Nicole Tee, Akiyoshi Uemura, Jonathan A. Epstein, Manvendra K. Singh

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Figure 6

Endothelium-specific Plxnd1 overexpression does not affect cardiac chamber development but can rescue the hypertrabeculation and noncompaction defects when crossed to a Plxnd1–/– background.

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Endothelium-specific Plxnd1 overexpression does not affect cardiac chamb...
Scheme of the endothelial-specific Plxnd1-transgenic construct (A). Transgenic founder (F0) mice were identified through PCR screening. Three 325-bp transgene-positive founders (white dotted box) were used for generating F1 (B). Western blot analysis of PlexinD1 for F2 control (transgene negative) and Tie2-Plxnd1-Tg embryo lysate. Anti-vinculin antibody is used as a loading control (C). Real-time qPCR for Plxnd1 using RNA isolated from endothelial cells of E10.5 control and Tie2-Plxnd1-Tg embryo (D). A transgenic line showing elevated levels of Plexind1 proteins was used for subsequent experiments. H&E staining of paraffin sections of E12.5 (n = 5 for each genotype) and E14.5 (n = 6 for each genotype) control and Tie2-Plxnd1-Tg hearts (E). H&E staining of paraffin sections of E15.5 Plxnd1–/– and Plxnd1–/– Tie2-Plxnd1-Tg hearts (F). (n = 4 for each genotype). LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. Scale bars: 100 μm.

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