The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1.

is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss of produces defects in somatic muscle and embryonic heart development, which have been partly attributed to directly targeting Delta to decrease Notch signaling. Here, we show that overexpression of in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potential targets revealed that directly regulates the 3'UTR of the E3 ubiquitin ligase Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development in Larval fly hearts overexpressing have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate that and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship between and the mammalian ortholog Nedd4-like () is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus, -mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.