Maternal loss of imprinting (LOI) at the H19/IGF2 locus results in biallelic IGF2 and reduced H19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance of Igf2 and H19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increased Igf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. These Igf2-dependent phenotypes are transient: cardiac size returns to normal once Igf2 expression is suppressed postnatally. However, reduced H19 expression is sufficient to cause progressive heart pathologies including fibrosis and reduced ventricular function. In the heart, H19 expression is primarily in endothelial cells (ECs) and regulates EC differentiation both, in vivo and in vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend on H19 lncRNA interactions with Mirlet7 microRNAs.
Sequencing data are deposited in the NCBI Gene Expression Omnibus (GEO) under series accession number GSE111418.
Mis-expression of Igf2 and H19 work independently on distinct cell types to cause cardiomyopathy in a Beckwtih Wiedemann mouse modelNCBI Gene Expression Omnibus, GSE111418.
- Karl Pfeifer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (050 and 063) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Surgery was performed under Avertin anesthesia and every effort was made to minimize suffering.
- Benjamin L Prosser, University of Pennsylvania Perelman School of Medicine, United States
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