Max Planck Institute for Heart and Lung Research, Department of Developmental Genetics, Bad Nauheim 61231, Germany.
Max Planck Institute for Heart and Lung Research, ECCPS Bioinformatics and Deep Sequencing Platform, Bad Nauheim 61231, Germany.
Development. 2018 May 17;145(10):dev159210. doi: 10.1242/dev.159210.
Cardiac trabeculation is a highly regulated process that starts with the delamination of compact layer cardiomyocytes. The Hippo signaling pathway has been implicated in cardiac development but many questions remain. We have investigated the role of Wwtr1, a nuclear effector of the Hippo pathway, in zebrafish and find that its loss leads to reduced cardiac trabeculation. However, in mosaic animals, cardiomyocytes contribute more frequently than cardiomyocytes to the trabecular layer of wild-type hearts. To investigate this paradox, we examined the myocardial wall at early stages and found that compact layer cardiomyocytes in hearts exhibit disorganized cortical actin structure and abnormal cell-cell junctions. Accordingly, wild-type cardiomyocytes in mosaic mutant hearts contribute less frequently to the trabecular layer than when present in mosaic wild-type hearts, indicating that hearts are not able to support trabeculation. We also found that Nrg/Erbb2 signaling, which is required for trabeculation, could promote Wwtr1 nuclear export in cardiomyocytes. Altogether, these data suggest that Wwtr1 establishes the compact wall architecture necessary for trabeculation, and that Nrg/Erbb2 signaling negatively regulates its nuclear localization and therefore its activity.
心脏小梁化是一个高度受调控的过程,始于致密层心肌细胞的分层。 Hippo 信号通路已被牵涉到心脏发育中,但仍有许多问题存在。我们研究了 Hippo 通路的核效应因子 Wwtr1 在斑马鱼中的作用,发现其缺失会导致心脏小梁化减少。然而,在嵌合体动物中, 心肌细胞比 心肌细胞更频繁地参与野生型心脏的小梁层形成。为了研究这个矛盾,我们在早期阶段检查了心肌壁,发现 心脏的致密层心肌细胞表现出皮质肌动蛋白结构紊乱和异常的细胞-细胞连接。因此,在嵌合体突变体心脏中,野生型心肌细胞形成小梁层的频率比存在于嵌合体野生型心脏中的频率要低,表明 心脏不能支持小梁化。我们还发现,Nrg/Erbb2 信号通路,它是小梁化所必需的,能够促进心肌细胞中 Wwtr1 的核输出。总之,这些数据表明 Wwtr1 建立了小梁化所必需的致密壁结构,并且 Nrg/Erbb2 信号通路负调控其核定位,从而负调控其活性。