Journal
DEVELOPMENTAL CELL
Volume 22, Issue 2, Pages 430-445Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2011.12.020
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Funding
- Swiss National Science Foundation [PPP0033-114898, 310030_127551]
- Leenaards Foundation
- Lymphatic Research Foundation
- Telethon Foundation
- Emma Muschamp Foundation
- German Research Foundation [SFB629, SFB656]
- Swiss National Science Foundation (SNF) [310030_127551] Funding Source: Swiss National Science Foundation (SNF)
- Grants-in-Aid for Scientific Research [24659603] Funding Source: KAKEN
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Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms. of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction.
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