Myc is dispensable for cardiomyocyte development but rescues Mycn-deficient hearts through functional replacement and...

Myc is considered an essential transcription factor for heart development, but cardiac defects have only been studied in global Myc loss-of-function models. Here, we eliminated Myc by recombining a Myc floxed allele with the Nkx2.5Cre driver. We observed no anatomical, cellular or functional alterations in either fetuses or adult cardiac Myc-deficient mice. We re-examined Myc expression during development and found no expression in developing cardiomyocytes. In contrast, we confirmed that Mycn is essential for cardiomyocyte proliferation and cardiogenesis. Mosaic Myc overexpression in a Mycn-deficient background shows that Myc can replace Mycn function, recovering heart development. We further show that this recovery involves the elimination of Mycn-deficient cells by cell competition. Our results indicate that Myc is dispensable in cardiomyocytes both during cardiogenesis and for adult heart homeostasis, and that Mycn is exclusively responsible for cardiomyocyte proliferation during heart development. Nonetheless, our results show that Myc can functionally replace Mycn We also show that cardiomyocytes compete according to their combined Myc and Mycn levels and that cell competition eliminates flawed cardiomyocytes, suggesting its relevance as a quality control mechanism in cardiac development.