Myc is dispensable for cardiomyocyte development but rescues Mycn-deficient hearts through functional replacement and cell competition
Myc is dispensable for cardiomyocyte development but rescues Mycn-deficient hearts through functional replacement and cell competition
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DOI：
10.1242/dev.170753
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发表时间：
2019-02-01
期刊：
影响因子：
4.6
通讯作者：
Torres, Miguel
中科院分区：
文献类型：
--
作者：
Munoz-Martin, Noelia;Sierra, Rocio;Torres, Miguel
MYC被认为是心脏发育所必需的转录因子，但心脏缺陷仅在全球Myc功能丧失模型中进行研究。在这里，我们通过将Myc的等位基因与Nkx2.5Cre驱动程序重组来消除Myc。我们没有观察到胎儿或成年心肌Myc缺陷小鼠的解剖、细胞或功能改变。我们重新检测了Myc在发育过程中的表达，发现在发育中的心肌细胞中没有表达。相反，我们证实Mycn对心肌细胞的增殖和心脏生成是必不可少的。在Mycn缺乏的背景下，嵌合体Myc的过度表达表明Myc可以取代Mycn的功能，恢复心脏发育。我们进一步表明，这种恢复包括通过细胞竞争消除Mycn缺陷的细胞。我们的结果表明，无论是在心脏发生过程中，还是在成人心脏动态平衡过程中，Myc在心肌细胞中都是必不可少的，Mycn是心脏发育过程中唯一负责心肌细胞增殖的基因。尽管如此，我们的结果表明，Myc在功能上可以取代Mycn。我们还表明，心肌细胞根据其结合的Myc和Mycn水平进行竞争，细胞竞争消除了有缺陷的心肌细胞，这表明它与心脏发育中的质量控制机制有关。
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.