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

Abstract

Dysregulation of the imprintedlocus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormalexpression 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 humanizedimprinting control region () on the paternal allele that exhibiteddysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role ofandin cardiac and placental development utilizing multiple mouse models with varying levels ofand. 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 ofdysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows thatdysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation byand, demonstrating that accurate dosage of bothandis critical for normal embryonic development, especially related to the cardiac-placental axis.