Slit-Robo Signaling Regulates the Development of the Cardiac Systemic Venous Return and Pericardium
Rationale: The Slit-Robo signaling pathway has pleiotropic functions during Drosophila heart development. However, its role in mammalian heart development is largely unknown.
Objective: To analyse the role of Slit-Robo signaling in the formation of the pericardium and the systemic venous return in the murine heart.
Methods and Results: Expression of genes encoding Robo1 and Robo2 receptors and their ligands Slit2 and Slit3 was found in or around the systemic venous return and pericardium during development. Analysis of embryos lacking Robo1 revealed partial absence of the pericardium, whereas Robo1/2 double mutants additionally showed severely reduced sinus horn myocardium, hypoplastic caval veins and a persistent left inferior caval vein. Mice lacking Slit3 recapitulated the defects in the myocardialization, alignment and morphology of the caval veins. Ligand binding assays confirmed Slit3 as the preferred ligand for the Robo1 receptor, whereas Slit2 showed preference for Robo2. Sinus node development was mostly unaffected in all mutants. Additionally, we show absence of cross-regulation with previously identified regulators Tbx18 and Wt1. We provide evidence that pericardial defects are created by abnormal localization of the caval veins combined with ectopic pericardial cavity formation. Local increase in neural crest cell death and impaired neural crest adhesive and migratory properties underlie the ectopic pericardium formation.
Conclusions: A novel Slit-Robo signaling pathway is involved in the development of the pericardium, the sinus horn myocardium and the alignment of the caval veins. Reduced Slit3 binding in absence of Robo1 causing impaired cardiac neural crest survival, adhesion and migration underlies the pericardial defects.
- Cardiac development
- Cardiac neural crest
- Heart development
- Slit-Robo signaling
- systemic venous return
- Received July 15, 2012.
- Accepted December 19, 2012.
- Copyright © 2012, American Heart Association