Open Biology ( IF 5.8 ) Pub Date : 2021-06-02 , DOI: 10.1098/rsob.210020 Chaohui Zhang 1 , Yuxin Li 1 , Jiaheng Cao 1 , Beibei Yu 1 , Kaiyue Zhang 1 , Ke Li 1 , Xinhui Xu 1 , Zhikun Guo 1 , Yinming Liang 2 , Xiao Yang 3 , Zhongzhou Yang 4 , Yunfu Sun 5 , Vesa Kaartinen 6 , Keyue Ding 7 , Jikui Wang 1
Smoothened is a key receptor of the hedgehog pathway, but the roles of Smoothened in cardiac development remain incompletely understood. In this study, we found that the conditional knockout of Smoothened from the mesoderm impaired the development of the venous pole of the heart and resulted in hypoplasia of the atrium/inflow tract (IFT) and a low heart rate. The blockage of Smoothened led to reduced expression of genes critical for sinoatrial node (SAN) development in the IFT. In a cardiac cell culture model, we identified a Gli2–Tbx5–Hcn4 pathway that controls SAN development. In the mutant embryos, the endocardial-to-mesenchymal transition (EndMT) in the atrioventricular cushion failed, and Bmp signalling was downregulated. The addition of Bmp2 rescued the EndMT in mutant explant cultures. Furthermore, we analysed Gli2+ scRNAseq and Tbx5−/− RNAseq data and explored the potential genes downstream of hedgehog signalling in posterior second heart field derivatives. In conclusion, our study reveals that Smoothened-mediated hedgehog signalling controls posterior cardiac progenitor commitment, which suggests that the mutation of Smoothened might be involved in the aetiology of congenital heart diseases related to the cardiac conduction system and heart valves.
中文翻译:
Hedgehog 信号控制窦房结发育和房室垫形成
Smoothened 是 Hedgehog 通路的关键受体,但 Smoothened 在心脏发育中的作用仍不完全清楚。在这项研究中,我们发现从中胚层条件性敲除Smoothened会损害心脏静脉极的发育,并导致心房/流入道 (IFT) 发育不全和心率低。Smoothened的堵塞导致 IFT 中对窦房结 (SAN) 发育至关重要的基因表达减少。在心脏细胞培养模型中,我们确定了控制 SAN 发育的 Gli2-Tbx5-Hcn4 通路。在突变胚胎中,房室垫中的心内膜间质转化 (EndMT) 失败,并且 Bmp 信号被下调。Bmp2 的添加挽救了突变外植体培养物中的 EndMT。此外,我们分析了Gli2 + scRNAseq 和Tbx5 -/- RNAseq 数据,并探索了后第二心脏场衍生物中刺猬信号下游的潜在基因。总之,我们的研究表明,Smoothened 介导的 Hedgehog 信号控制后部心脏祖细胞的承诺,这表明Smoothened可能与心脏传导系统和心脏瓣膜相关的先天性心脏病的病因有关。