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Significance Myocardium thickening at midgestation to late gestation is crucial for the formation of a functionally competent postnatal heart. However, posttranslational mechanisms regulating this process remain unexplored. Here, we uncover a critical role for the ubiquitin-like protein NEDD8 in heart development. By targeting the E1 enzyme that mediates the conjugation of NEDD8 to protein targets, we show that NEDD8 modification is essential for ventricular compaction and heart function. We further identify that the NEDD8 substrate Cullin 7 mediates the degradation of Hippo kinase Mst1, thereby enabling YAP signaling, cardiomyocyte proliferation, and proper heart development. These results reveal a posttranslational regulatory mechanism in ventricular wall maturation and may provide mechanistic insights into the etiology of left ventricular noncompaction cardiomyopathy.

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling