Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany; International Graduate School in Molecular Medicine Ulm, Ulm University, 89081 Ulm, Germany.
Klinik und Poliklinik für Innere Medizin I, Klinikum Rechts der Isar der Technischen Universität München, Ismaninger Strasse 22, 81675 Munich, Germany.
Dev Biol. 2019 May 1;449(1):1-13. doi: 10.1016/j.ydbio.2019.02.009. Epub 2019 Feb 21.
Wnt proteins can activate different intracellular signaling pathways. These pathways need to be tightly regulated for proper cardiogenesis. The canonical Wnt/β-catenin inhibitor Dkk1 has been shown to be sufficient to trigger cardiogenesis in gain-of-function experiments performed in multiple model systems. Loss-of-function studies however did not reveal any fundamental function for Dkk1 during cardiogenesis. Using Xenopus laevis as a model we here show for the first time that Dkk1 is required for proper differentiation of cardiomyocytes, whereas specification of cardiomyocytes remains unaffected in absence of Dkk1. This effect is at least in part mediated through regulation of non-canonical Wnt signaling via Wnt11. In line with these observations we also found that Isl1, a critical regulator for specification of the common cardiac progenitor cell (CPC) population, acts upstream of Dkk1.
Wnt 蛋白可以激活不同的细胞内信号通路。这些通路需要被严格调控,以保证心脏的正常发生。已经有研究表明,在多个模型系统的功能获得实验中,经典 Wnt/β-连环蛋白抑制剂 Dkk1 足以触发心脏发生。然而,功能丧失研究并未揭示 Dkk1 在心脏发生过程中的任何基本功能。在这里,我们首次使用非洲爪蟾(Xenopus laevis)作为模型,表明 Dkk1 对于心肌细胞的正常分化是必需的,而在没有 Dkk1 的情况下,心肌细胞的特化仍然不受影响。这种效应至少部分是通过调节非经典 Wnt 信号通路来介导的,该通路通过 Wnt11 进行调节。与这些观察结果一致,我们还发现,对于共同心脏祖细胞(CPC)群体的特化的关键调节因子 Isl1,位于 Dkk1 的上游。