Intricate MIB1-NOTCH-GATA6 Interactions in Cardiac Valvular and Septal Development.

Abstract

Genome-wide association studies and experimental mouse models implicate the and genes in congenital heart disease (CHD). Their close physical proximity and conserved synteny suggest that these two genes might be involved in analogous cardiac developmental processes. Heterozygous loss-of-function mutations alone or humanized mutations in a NOTCH1-sensitized genetic background cause bicuspid aortic valve (BAV) and a membranous ventricular septal defect (VSD), consistent with MIB1 and NOTCH1 functioning in the same pathway. To determine if MIB1-NOTCH and GATA6 interact in valvular and septal development, we generated compound heterozygote mice carrying different Mib1 ( and ) or () mutations with the heterozygous null mutation. Combining or with does not affect single mutant phenotypes. In contrast, combining with decreases the incidence of BAV and VSD by 50%, suggesting a suppressive effect of on . Transcriptomic and functional analyses revealed that while the EMT pathway term is depleted in the mutant, introducing the variant robustly enriches this term, consistent with the phenotypic suppression of . Interestingly, combined and insufficiency led to a nearly fully penetrant VSD but did not affect the BAV phenotype, underscoring the complex functional relationship between MIB1, NOTCH, and GATA6 in valvular and septal development.