title: DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C.
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.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Sarah
authors.identifier: 0000-0003-1676-8770
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Lothar C
authors.initials: LC
authors.lastname: Dieterich
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mathelier
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Chloé
authors.initials: C
authors.lastname: Chong
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sliwa-Primorac
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Hong
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Shin
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Lizio
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: 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.
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Carsten O
authors.initials: CO
authors.lastname: Daub
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.affiliation: RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.affiliation: 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.
authors.forename: Alistair R R
authors.identifier: 0000-0003-4543-1675
authors.initials: AR
authors.lastname: Forrest
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich 8093, Switzerland michael.detmar@pharma.ethz.ch.
authors.forename: Michael
authors.identifier: 0000-0002-5351-5054
authors.initials: M
authors.lastname: Detmar
mesh_terms: D002460:Cell Line; D002463:Cell Membrane Permeability / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C; C072064:HOXD10 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: HOXD10; Immediate early gene; Lymphangiogenesis; Lymphatic endothelium; Transcription factor; VEGFR-3