DysregulatedH19/Igf2expression disrupts cardiac-placental axis during development of Silver Russell Syndrome-like mouse models

Dysregulation of the imprintedH19/IGF2locus can lead to Silver-Russell Syndrome (SRS) in humans. However, the mechanism of how abnormalH19/IGF2expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanizedH19/IGF2ICR (hIC1) on the paternal allele that exhibitedH19/Igf2dysregulation together with SRS-like growth restriction and perinatal lethality. Here we dissect the role ofH19andIgf2in cardiac and placental development utilizing multiple mouse models with varying levels ofH19andIgf2. We report severe cardiac defects such as ventricular septal defects (VSDs) and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent ofH19/Igf2dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows thatH19/Igf2dysregulation disrupts pathways related to extracellular matrix (ECM) and proliferation of endothelial cells. Our work links the heart and placenta through regulation byH19andIgf2, demonstrating that accurate dosage of bothH19andIgf2is critical for normal embryonic development, especially related to the cardiac-placental axis.