Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation
| العنوان: | Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation |
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| المؤلفون: | Ardem Patapoutian, Akemi Kanie, Sanjeev S. Ranade, Tess Whitwam, Mark L. Kahn, Toshihiko Fujimori, Daniel T. Sweet, Keiko Nonomura, Viktor Lukacs, Lauren M. Goddard |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Physiology, government.form_of_government, lymphatic system, Ion Channels, Congenital lymphedema, valve formation, 03 medical and health sciences, Mice, Antigens, CD, Cell Movement, Cell Adhesion, Animals, Mechanotransduction, Lymphangiogenesis, Actin, mechanotransduction, Lymphatic Vessels, Multidisciplinary, Ion Transport, biology, NFATC Transcription Factors, Chemistry, PIEZO1, Endothelial Cells, Forkhead Transcription Factors, Actomyosin, Biological Sciences, Cadherins, Cell biology, Lymphatic Endothelium, 030104 developmental biology, Lymphatic system, Intercellular Junctions, ion channel, government, biology.protein, Lymph, FOXC2, Signal Transduction, Transcription Factors |
| الوصف: | Significance PIEZOs are mechanically activated cation channels. Recently, loss-of-function mutations of human PIEZO1 were found among patients with familial lymphedema, suggesting a requirement of PIEZO1 in the lymphatic system. In this paper, utilizing mouse models lacking PIEZO1 in endothelial cells, we show that this ion channel is required for the formation of lymphatic valves, a key structure for proper circulation of lymph in the body. The requirement of PIEZO1 in valve formation provides mechanistic insight on how PIEZO1 variants cause lymphatic dysfunction in patients. This study also extends the relevance of PIEZOs beyond acute signaling molecules (e.g., touch sensation) and highlights the importance of these ion channels in controlling morphological/structural specification during development. PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell–cell junctions, was impaired in Tie2Cre;Piezo1cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell–cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c8e94b3c1140bec0d011e15065221398 http://europepmc.org/articles/PMC6294938 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c8e94b3c1140bec0d011e15065221398 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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