Institute of Biochemistry and Biology, Potsdam University, 14476 Potsdam, Germany.
Institute of Biochemistry and Biology, Potsdam University, 14476 Potsdam, Germany; Institute of Molecular Biology, Hannover Medical School, 30625 Hannover, Germany.
Cell Rep. 2021 Oct 5;37(1):109782. doi: 10.1016/j.celrep.2021.109782.
In the zebrafish embryo, the onset of blood flow generates fluid shear stress on endocardial cells, which are specialized endothelial cells that line the interior of the heart. High levels of fluid shear stress activate both Notch and Klf2 signaling, which play crucial roles in atrioventricular valvulogenesis. However, it remains unclear why only individual endocardial cells ingress into the cardiac jelly and initiate valvulogenesis. Here, we show that lateral inhibition between endocardial cells, mediated by Notch, singles out Delta-like-4-positive endocardial cells. These cells ingress into the cardiac jelly, where they form an abluminal cell population. Delta-like-4-positive cells ingress in response to Wnt9a, which is produced in parallel through an Erk5-Klf2-Wnt9a signaling cascade also activated by blood flow. Hence, mechanical stimulation activates parallel mechanosensitive signaling pathways that produce binary effects by driving endocardial cells toward either luminal or abluminal fates. Ultimately, these cell fate decisions sculpt cardiac valve leaflets.
在斑马鱼胚胎中，血流的开始会对心内膜细胞产生流体切应力，心内膜细胞是专门的内皮细胞，排列在心脏内部。高水平的流体切应力会激活 Notch 和 Klf2 信号通路，这两个信号通路在房室瓣膜发生中起着至关重要的作用。然而，目前尚不清楚为什么只有个别心内膜细胞进入心胶质并启动瓣膜发生。在这里，我们表明 Notch 介导的心内膜细胞之间的侧向抑制作用，挑选出 Delta-like-4 阳性的心内膜细胞。这些细胞进入心胶质，在那里形成一个心外膜细胞群体。Delta-like-4 阳性细胞对 Wnt9a 作出反应，Wnt9a 通过同样由血流激活的 Erk5-Klf2-Wnt9a 信号级联反应平行产生。因此，机械刺激激活了平行的机械敏感信号通路，通过将心内膜细胞推向管腔或心外膜命运来产生二元效应。最终，这些细胞命运决定塑造了心脏瓣膜叶。
