Slit-roundabout signaling regulates the development of the cardiac systemic venous return and pericardium
| Autor: | Alain Chédotal, Mathilda T.M. Mommersteeg, Mason L. Yeh, William D. Andrews, Pavol Zelina, Vincent M. Christoffels, John G. Parnavelas, Julia Norden, Andreas Kispert, Athena R. Ypsilanti |
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| Přispěvatelé: | Amsterdam Cardiovascular Sciences, Amsterdam Reproduction & Development (AR&D), Medical Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Heart Defects
Congenital Pathology medicine.medical_specialty Physiology Apoptosis Gestational Age Nerve Tissue Proteins Biology Tissue Culture Techniques Mice Cell Movement ROBO1 Cell Adhesion Morphogenesis medicine SLIT2 Animals Pericardium cardiovascular diseases Receptors Immunologic WT1 Proteins Vein Sinoatrial Node Mice Knockout Mice Inbred C3H Heart development Pericardial cavity Gene Expression Regulation Developmental Membrane Proteins Neural crest Mice Inbred C57BL medicine.anatomical_structure Neural Crest cardiovascular system Intercellular Signaling Peptides and Proteins Venae Cavae T-Box Domain Proteins Cardiology and Cardiovascular Medicine Venous return curve Signal Transduction |
| Zdroj: | Circulation research, 112(3), 465-475. Lippincott Williams and Wilkins |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Rationale: The Slit–Roundabout (Robo) signaling pathway has pleiotropic functions during Drosophila heart development. However, its role in mammalian heart development is largely unknown. Objective: To analyze 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. In addition, 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 the absence of Robo1, causing impaired cardiac neural crest survival, adhesion, and migration, underlies the pericardial defects. |
| Databáze: | OpenAIRE |
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