Notch signaling regulates smooth muscle differentiation of epicardium-derived cells.
BACKGROUND
The embryonic epicardium plays a crucial role in the formation of the coronary vasculature and in myocardial development, yet the exact contribution of epicardium-derived cells (EPDCs) to the vascular and connective tissue of the heart, and the factors that regulate epicardial differentiation, are insufficiently understood.


OBJECTIVE
To define the role of Notch signaling in murine epicardial development.


RESULTS
Using in situ hybridization and RT-PCR analyses, we detected expression of a number of Notch receptor and ligand genes in early epicardial development, as well as during formation of coronary arteries. Mice with epicardial deletion of Rbpj, the unique intracellular mediator of Notch signaling, survived to adulthood and exhibited enlarged coronary venous and arterial beds. Using a Tbx18-based genetic lineage tracing system, we show that EPDCs give rise to fibroblasts and coronary smooth muscle cells (SMCs) but not to endothelial cells in the wild type, whereas in Rbpj-deficient embryos EPDCs form and surround the developing arteries but fail to differentiate into SMCs. Conditional activation of Notch signaling results in premature SMC differentiation of epicardial cells and prevents coronary angiogenesis. We further show that Notch signaling regulates, and cooperates with transforming growth factor β signaling in SM differentiation of EPDCs.


CONCLUSIONS
Notch signaling is a crucial regulator of SM differentiation of EPDCs, and thus, of formation of a functional coronary system.
Institut für Molekularbiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, Hannover, Germany.
Thomas
T
Grieskamp
Carsten
C
Rudat
Timo H-W
TH
Lüdtke
Julia
J
Norden
Andreas
A
Kispert
D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000503:physiopathology; D005260:Female; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010496:Pericardium / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D020797:Receptor, Platelet-Derived Growth Factor beta