DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C

S. Klein, L.C. Dieterich, A. Mathelier, C. Chong, A. Sliwa-Primorac, Y.K. Hong, J.W. Shin, M. Lizio, M. Itoh, H. Kawaji, Timo Lassmann, C.O. Daub, E. Arner, P. Carninci, Y. Hayashizaki, Alistair Forrest, W.W. Wasserman, M. Detmar

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


© 2016. Published by The Company of Biologists Ltd.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.
Original languageEnglish
Pages (from-to)2573-2585
JournalJournal of Cell Science
Issue number13
Publication statusPublished - 2016


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