Dysregulated expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models.

Dysregulation of the imprinted locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal expression 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 humanized imprinting control region () on the paternal allele that exhibited dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of and in cardiac and placental development utilizing multiple mouse models with varying levels of and . We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by and , demonstrating that accurate dosage of both and is critical for normal embryonic development, especially related to the cardiac-placental axis.