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The  Nkx2‐5  gene codes for a transcription factor that plays a critical role in heart development. Heterozygous mutations in  NKX2‐5  in both human and mice result in congenital heart defects (CHDs). However, the molecular mechanisms by which these mutations cause the disease are still unknown. Recently, we have generated the heterozygous mouse model of the human CHDs associated mutation  NKX2‐5 R142C  ( Nkx2‐5 R141C/+   mouse ortholog of human NKX2‐5 R142C variant) that developed septal and conduction defects. This study generated a heterozygous  Nkx2‐5 R141C  mouse embryonic stem cell line ( Nkx2‐5 R141C/+   mESCs) to model CHDs in vitro. We observed that  Nkx2‐5 R141C/+   mESCs display an alteration in the expression of genes that are essential for normal heart development. Furthermore, the reduced cardiomyogenesis is paralleled by a reduction in nuclear import of Nkx2‐5 protein. Examination of the  Nkx2‐5 R141C/+   embryos at E8.5 revealed a transient loss of cardiomyogenesis, which is consistent with the phenotype observed in vitro. Moreover, gene expression profiling of  Nkx2‐5 R141C/+   cells at an early stage of cardiac differentiation revealed pronounced deregulation of several cardiac differentiation and function genes. Collectively, our data showed that heterozygosity for the R141C mutation results in disruption of the cellular distribution of Nkx2‐5 protein, a transient reduction in cardiomyogenesis that may disrupt the early patterning of the heart, and this, in turn, affects the intricate orchestration of signaling pathways leading to downregulation of Bone morphogenetic protein (BMP) and Notch signaling. Therefore, we have developed mESCs model of a human CHD, providing an in vitro system to examine early stages of heart development, which are otherwise difficult to study in vivo. S tem  C ells   2018;36:514–526

In Vitro Modeling of Congenital Heart Defects Associated with an NKX2‐5 Mutation Revealed a Dysregulation in BMP/Notch‐Mediated Signaling