Journal
JOURNAL OF CELL SCIENCE
Volume 129, Issue 13, Pages 2573-2585Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.186767
Keywords
HOXD10; Transcription factor; Lymphatic endothelium; Lymphangiogenesis; VEGFR-3; Immediate early gene
Categories
Funding
- Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) [310030B_147087]
- European Research Council
- Oncosuisse
- Lymph Vessels in Obesity and Cardiovascular Disease grant from the Krebsliga Schweiz
- Fondation Leducq (Zurich and Leducq Foundation Transatlantic Network of Excellence) [11CVD03]
- Genome Canada [174CDE]
- BC Children's Hospital Foundation
- Child and Family Research Institute, Vancouver, Canada
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Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 (also known as FLT4) by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors that are upregulated in human lymphatic endothelial cells (LECs) within the first 30 to 80 min after VEGFR-3 activation. Expression of these transcription factors must be regulated by additional pre-existing transcription factors that are rapidly activated by VEGFR-3 signaling. Using transcription factor activity analysis, we identified the homeobox transcription factor HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early transcription factors, including NR4A1. Gain- and loss-of-function studies revealed that HOXD10 is involved in LECs migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and NOS3 (also known as e-NOS), and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability.
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