Hedgehog signalling controls sinoatrial node development and atrioventricular cushion formation

• Published in: Open biology 2021-06, Vol.11 (6), p.210020-210020
• Main Authors: Zhang, Chaohui, Li, Yuxin, Cao, Jiaheng, Yu, Beibei, Zhang, Kaiyue, Li, Ke, Xu, Xinhui, Guo, Zhikun, Liang, Yinming, Yang, Xiao, Yang, Zhongzhou, Sun, Yunfu, Kaartinen, Vesa, Ding, Keyue, Wang, Jikui
• Format: Article
• Language: English
• Subjects: Animals; atrioventricular cushion; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - metabolism; Computational Biology - methods; Endocardial Cushions - embryology; Endocardial Cushions - metabolism; Fluorescent Antibody Technique; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Ontology; Hedgehog Proteins - metabolism; hedgehog signalling; Immunohistochemistry; inflow tract; Mice; Mice, Knockout; Mice, Transgenic; Organogenesis; Signal Transduction; sinoatrial node; Sinoatrial Node - embryology; Sinoatrial Node - metabolism; Smoothened; Smoothened Receptor - genetics; Smoothened Receptor - metabolism; Tbx5
• ISSN: 2046-2441; 2046-2441
• DOI: 10.1098/rsob.210020

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 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 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 scRNAseq and 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 might be involved in the aetiology of congenital heart diseases related to the cardiac conduction system and heart valves.