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J Cell Sci. 2016 Jul 1;129(13):2573-85. doi: 10.1242/jcs.186767. Epub 2016 May 19.

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

Author information

1
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
2
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
3
Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
4
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
5
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia 6008, Australia.
6
RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.
7
RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan Cancer and Cell Biology Division, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, the University of Western Australia, Nedlands, Western Australia 6009, Australia.
8
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland michael.detmar@pharma.ethz.ch.

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-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.

KEYWORDS:

HOXD10; Immediate early gene; Lymphangiogenesis; Lymphatic endothelium; Transcription factor; VEGFR-3

PMID:
27199372
DOI:
10.1242/jcs.186767
[Indexed for MEDLINE]
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