Inhibition of cardiomyocyte neddylation impairs embryonic cardiac morphogenesis

Heart development is a complex spatiotemporal process involving a series of orchestrated morphogenic events that result in the formation of an efficient pumping organ. How posttranslational mechanisms regulate heart development remains poorly understood. Therefore, we investigate how neddylation, the attachment of NEDD8 to target proteins, coordinates cardiogenesis. Abrogation of neddylation by deleting Nae1 in the heart via Sm22αCre led to early embryonic lethality. Mutant hearts exhibited deficits in trabeculation and expansion of the compact layer due to reduced cardiomyocyte proliferation, which was linked to abnormal Notch signaling in the developing heart. Overall, our findings demonstrate an essential role for neddylation in cardiogenesis. [Display omitted] •Neddylation is an emerging post-translational protein modification.•Deletion of Nae1 (NEDD8-activating enzyme E1 subunit 1) via Sm22αCre is sufficient to abolish neddylation in the heart.•Inhibition of neddylation results in myocardial hypoplasia and embryonic lethality.•Neddylation is required for cardiomyocyte proliferation and the fine-tuning of Notch signaling.•Neddylation is a crucial post-translational mechanism that regulates cardiogenesis.