Authors:
Klein S, Dieterich LC, Mathelier A, Chong C, Sliwa-Primorac A, Hong YK, ... Lassmann T, et al.
Authors notes:
Journal of Cell Science. 2016;129(13):2573-85.
Keywords:
HOXD10, Immediate early gene, Lymphangiogenesis, Lymphatic endothelium, Transcription factor, VEGFR-3, lymphatic endothelial cells (LECs)
Abstract:
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-offunction 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.