Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway

• DOI: 10.7554/elife.97268
• Publication Date: 2024-06-05T13:34:50Z
• Authors: Yunfei Mu; Shijia Hu; Xiangyang Liu; Xin Tang; Jiayi Lin; Hongjun Shi
• Keywords: mTORC2

Notch signaling has been identified as a key regulatory pathway in patterning the endocardium through activation of endothelial-to-mesenchymal transition (EMT) atrioventricular canal (AVC) and proximal outflow tract (OFT) region. However, precise mechanism underlying remains elusive. By transiently blocking heartbeat E9.5 mouse embryos, we found that arterial endothelium was dependent on its ligand Dll4, whereas reduced expression Dll4 led to ligand-depleted field, enabling be specifically activated AVC OFT by regional increased shear stress. The strong stress altered membrane lipid microdomain structure endocardial cells, which mTORC2 PKC promoted Notch1 cleavage even absence stimulation. These findings highlight role mechanical forces primary cue for provide insights into mechanisms congenital heart diseases origin.