Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
Division of Molecular and Developmental Biology, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
Nat Commun. 2017 Feb 17;8:14495. doi: 10.1038/ncomms14495.
Tissue integrity is critical for organ formation and function. During heart development, cardiomyocytes differentiate and integrate to form a coherent tissue that contracts synchronously. However, the molecular mechanisms regulating cardiac tissue integrity are poorly understood. Here we show that proteolysis, via the E3 ubiquitin ligase ASB2, regulates cardiomyocyte maturation and tissue integrity. Cardiomyocytes in asb2b zebrafish mutants fail to terminally differentiate, resulting in reduced cardiac contractility and output. Mosaic analyses reveal a cell-autonomous requirement for Asb2b in cardiomyocytes for their integration as asb2b mutant cardiomyocytes are unable to meld into wild-type myocardial tissue. In vitro and in vivo data indicate that ASB2 negatively regulates TCF3, a bHLH transcription factor. TCF3 must be degraded for cardiomyocyte maturation, as TCF3 gain-of-function causes a number of phenotypes associated with cardiomyocyte dedifferentiation. Overall, our results show that proteolysis has an important role in cardiomyocyte maturation and the formation of a coherent myocardial tissue.
组织完整性对于器官的形成和功能至关重要。在心脏发育过程中，心肌细胞分化并整合形成一个协调收缩的连贯组织。然而，调节心脏组织完整性的分子机制还知之甚少。在这里，我们表明蛋白酶体通过 E3 泛素连接酶 ASB2 来调节心肌细胞的成熟和组织完整性。asb2b 斑马鱼突变体中的心肌细胞不能终末分化，导致心肌收缩力和输出减少。嵌合体分析显示，Asb2b 在心肌细胞中具有细胞自主性整合要求，因为 asb2b 突变型心肌细胞无法融入野生型心肌组织。体外和体内数据表明，ASB2 负调控 bHLH 转录因子 TCF3。TCF3 必须被降解才能使心肌细胞成熟，因为 TCF3 的功能获得会导致许多与心肌细胞去分化相关的表型。总的来说，我们的结果表明蛋白酶体在心肌细胞成熟和形成协调的心肌组织中具有重要作用。
