Notch signalling in ventricular chamber development and cardiomyopathy

• Published in: The FEBS journal 2016-12, Vol.283 (23), p.4223-4237
• Main Authors: D'Amato, Gaetano, Luxán, Guillermo, Pompa, José Luis
• Format: Article
• Language: English
• Subjects: Animals; Cardiology; Cardiomyopathies - embryology; Cardiomyopathies - metabolism; Cardiomyopathy; compaction; Endocardium - embryology; Endocardium - metabolism; heart; Heart Ventricles - embryology; Heart Ventricles - metabolism; Humans; left ventricular noncompaction; Microbiology; Models, Cardiovascular; Myocardium - metabolism; NOTCH; Organogenesis; Receptors, Notch - metabolism; Signal Transduction; signalling; trabeculae; ventricles
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13773

The vertebrate heart is the first organ to form and function during embryogenesis. Primitive streak‐derived cardiac progenitors located bilaterally move rostral to form the primitive heart tube that subsequently undergoes rightward looping, remodelling and septation to give rise to the mature four‐chambered heart. Tightly regulated tissue interactions orchestrate the patterning, proliferation and differentiation processes that give rise to the adult ventricles. Studies in animal models have demonstrated the crucial function of the Notch signalling pathway in ventricular development and how alterations in human NOTCH signalling may lead to disease in the form of cardiomyopathies, such as left ventricular noncompaction (LVNC). In this review, we discuss how during trabecular formation and ventricular compaction, Dll4–Notch1 signals from chamber endocardium to regulate cardiomyocyte proliferation and differentiation in a noncell autonomous fashion and how, at later stages, myocardial Jag1 and Jag2 activate Notch1 in chamber endocardium to sustain chamber patterning and compaction with simultaneous coronary vessel development mediated by Dll4–Notch1. We suggest that alterations in these molecular mechanisms underlie MIB1‐related familial LVNC and favour the hypothesis that this cardiomyopathy has a congenital nature. Endocardial Notch1 activity is indispensable for cardiac chamber morphogenesis. Post‐translational modification of the Notch1 receptor mediated by the glycosyltransferase manic fringe, and the different spatio‐temporal expression pattern of the Mib1‐dependent ligands Dll4, Jag1 and Jag2 determine the sequential activation of Notch1 in the endocardium. Perturbation of this signalling process severely disrupts trabeculation and compaction, leading to left ventricular noncompaction cardiomyopathy.