Essentiality of Regulator of G Protein Signaling 6 and Oxidized Ca2+/Calmodulin‐Dependent Protein Kinase II in Notch Signaling and Cardiovascular Development

BackgroundCongenital heart defects are the most common birth defects worldwide. Although defective Notch signaling is the major cause of mouse embryonic death from cardiovascular defects, how Notch signaling is regulated during embryonic vasculogenesis and heart development is poorly understood. Methods and ResultsRegulator of G protein signaling 6 (RGS6)−/−/Ca2+/calmodulin‐dependent protein kinase II (CaMKII)VV double mutant mice were developed by crossing RGS6−/− mice with mice expressing an oxidation‐resistant CaMKIIδ (CaMKIIVV), and the resulting embryonic defects/lethality were investigated using E7.5 to E15.5 embryos. While loss of either RGS6 or oxidized CaMKIIδ does not alter embryogenesis, their combined loss causes defective Notch signaling, severe cardiovascular defects, and embryonic lethality (≈E10.5–11.5). Embryos lacking RGS6 and expressing oxidation‐resistant CaMKIIδ exhibit reduced myocardial wall thickness, abnormal trabeculation, and arterial specification defects. Double mutants show v...