Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway
Notch signaling has been identified as a key regulatory pathway in patterning the endocardium through activation of endothelial-to-mesenchymal transition (EMT) in the atrioventricular canal (AVC) and proximal outflow tract (OFT) region. However, the precise mechanism underlying Notch activation rema...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/97268 |
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| author | Yunfei Mu Shijia Hu Xiangyang Liu Xin Tang Jiayi Lin Hongjun Shi |
| author_facet | Yunfei Mu Shijia Hu Xiangyang Liu Xin Tang Jiayi Lin Hongjun Shi |
| author_sort | Yunfei Mu |
| collection | DOAJ |
| description | Notch signaling has been identified as a key regulatory pathway in patterning the endocardium through activation of endothelial-to-mesenchymal transition (EMT) in the atrioventricular canal (AVC) and proximal outflow tract (OFT) region. However, the precise mechanism underlying Notch activation remains elusive. By transiently blocking the heartbeat of E9.5 mouse embryos, we found that Notch activation in the arterial endothelium was dependent on its ligand Dll4, whereas the reduced expression of Dll4 in the endocardium led to a ligand-depleted field, enabling Notch to be specifically activated in AVC and OFT by regional increased shear stress. The strong shear stress altered the membrane lipid microdomain structure of endocardial cells, which activated mTORC2 and PKC and promoted Notch1 cleavage even in the absence of strong ligand stimulation. These findings highlight the role of mechanical forces as a primary cue for endocardial patterning and provide insights into the mechanisms underlying congenital heart diseases of endocardial origin. |
| format | Article |
| id | doaj-art-0dec6c63e89643cea4308d10cec22086 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-0dec6c63e89643cea4308d10cec220862025-02-11T14:33:23ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.97268Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathwayYunfei Mu0https://orcid.org/0009-0003-3749-3718Shijia Hu1Xiangyang Liu2Xin Tang3Jiayi Lin4Hongjun Shi5https://orcid.org/0000-0002-4993-2322Fudan University, Shanghai, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaFudan University, Shanghai, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaKey Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, ChinaNotch signaling has been identified as a key regulatory pathway in patterning the endocardium through activation of endothelial-to-mesenchymal transition (EMT) in the atrioventricular canal (AVC) and proximal outflow tract (OFT) region. However, the precise mechanism underlying Notch activation remains elusive. By transiently blocking the heartbeat of E9.5 mouse embryos, we found that Notch activation in the arterial endothelium was dependent on its ligand Dll4, whereas the reduced expression of Dll4 in the endocardium led to a ligand-depleted field, enabling Notch to be specifically activated in AVC and OFT by regional increased shear stress. The strong shear stress altered the membrane lipid microdomain structure of endocardial cells, which activated mTORC2 and PKC and promoted Notch1 cleavage even in the absence of strong ligand stimulation. These findings highlight the role of mechanical forces as a primary cue for endocardial patterning and provide insights into the mechanisms underlying congenital heart diseases of endocardial origin.https://elifesciences.org/articles/97268cardiac patterningendocardiumEMTnotchshear stressmechanosensing |
| spellingShingle | Yunfei Mu Shijia Hu Xiangyang Liu Xin Tang Jiayi Lin Hongjun Shi Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway eLife cardiac patterning endocardium EMT notch shear stress mechanosensing |
| title | Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway |
| title_full | Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway |
| title_fullStr | Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway |
| title_full_unstemmed | Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway |
| title_short | Mechanical forces pattern endocardial Notch activation via mTORC2-PKC pathway |
| title_sort | mechanical forces pattern endocardial notch activation via mtorc2 pkc pathway |
| topic | cardiac patterning endocardium EMT notch shear stress mechanosensing |
| url | https://elifesciences.org/articles/97268 |
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