Cardiac pathologies in mouse loss of imprinting models are due to misexpression of H19 long noncoding RNA

Maternal loss of imprinting (LOI) at theH19/IGF2 locus results in biallelicIGF2 and reducedH19 expression and is associated with Beckwith-Wiedemann syndrome (BWS). We use mouse models for LOI to understand the relative importance ofIgf2 andH19 mis-expression in BWS phenotypes. Here we focus on cardiovascular phenotypes and show that neonatal cardiomegaly is exclusively dependent on increasedIgf2. Circulating IGF2 binds cardiomyocyte receptors to hyperactivate mTOR signaling, resulting in cellular hyperplasia and hypertrophy. TheseIgf2-dependent phenotypes are transient: cardiac size returns to normal onceIgf2 expression is suppressed postnatally. However, reducedH19 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 andin vitro. Finally, we establish novel mouse models to show that cardiac phenotypes depend onH19 lncRNA interactions withMirlet7microRNAs.
Source: eLife - Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research