Hempel Annemarie, Kühl Susanne J, Rothe Melanie, Rao Tata Purushothama, Sirbu Ioan Ovidiu, Vainio Seppo J, Kühl Michael
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany; International Graduate School in Molecular Medicine Ulm, IGradU, Ulm University, 89069 Ulm, Germany.
Institute of Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
Dev Biol. 2017 Apr 1;424(1):28-39. doi: 10.1016/j.ydbio.2017.02.014. Epub 2017 Feb 22.
Wnt proteins are critical for embryonic cardiogenesis and cardiomyogenesis by regulating different intracellular signalling pathways. Whereas canonical Wnt/β-catenin signalling is required for mesoderm induction and proliferation of cardiac progenitor cells, β-catenin independent, non-canonical Wnt signalling regulates cardiac specification and terminal differentiation. Although the diverse cardiac malformations associated with the loss of non-canonical Wnt11 in mice such as outflow tract (OFT) defects, reduced ventricular trabeculation, myofibrillar disorganization and reduced cardiac marker gene expression are well described, the underlying molecular mechanisms are still not completely understood. Here we aimed to further characterize Wnt11 mediated signal transduction during vertebrate cardiogenesis. Using Xenopus as a model system, we show by loss of function and corresponding rescue experiments that the non-canonical Wnt signalling mediator Rcsd1 is required downstream of Wnt11 for ventricular trabeculation, terminal differentiation of cardiomyocytes and cardiac morphogenesis. We here place Rcsd1 downstream of Wnt11 during cardiac development thereby providing a novel mechanism for how non-canonical Wnt signalling regulates vertebrate cardiogenesis.
Wnt蛋白通过调节不同的细胞内信号通路,对胚胎心脏发生和心肌发生至关重要。经典的Wnt/β-连环蛋白信号通路是中胚层诱导和心脏祖细胞增殖所必需的,而β-连环蛋白非依赖性的非经典Wnt信号通路则调节心脏特化和终末分化。尽管与小鼠中非经典Wnt11缺失相关的多种心脏畸形,如流出道(OFT)缺陷、心室小梁减少、肌原纤维紊乱和心脏标记基因表达降低等已得到充分描述,但其潜在的分子机制仍未完全了解。在这里,我们旨在进一步表征脊椎动物心脏发生过程中Wnt11介导的信号转导。以非洲爪蟾作为模型系统,我们通过功能丧失和相应的拯救实验表明,非经典Wnt信号介导因子Rcsd1在Wnt11下游对于心室小梁形成、心肌细胞终末分化和心脏形态发生是必需的。我们在此确定了Rcsd1在心脏发育过程中位于Wnt11下游,从而为非经典Wnt信号如何调节脊椎动物心脏发生提供了一种新机制。