title: DeepCAGE Transcriptomics Reveal an Important Role of the Transcription Factor MAFB in the Lymphatic Endothelium.
abstract: VEGF-C/VEGFR-3 signaling plays a central role in lymphatic development, regulating the budding of lymphatic progenitor cells from embryonic veins and maintaining the expression of PROX1 during later developmental stages. However, how VEGFR-3 activation translates into target gene expression is still not completely understood. We used cap analysis of gene expression (CAGE) RNA sequencing to characterize the transcriptional changes invoked by VEGF-C in LECs and to identify the transcription factors (TFs) involved. We found that MAFB, a TF involved in differentiation of various cell types, is rapidly induced and activated by VEGF-C. MAFB induced expression of PROX1 as well as other TFs and markers of differentiated LECs, indicating a role in the maintenance of the mature LEC phenotype. Correspondingly, E14.5 Mafb(-/-) embryos showed impaired lymphatic patterning in the skin. This suggests that MAFB is an important TF involved in lymphangiogenesis.
authors.affiliation: Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.
authors.forename: Lothar C
authors.initials: LC
authors.lastname: Dieterich
authors.affiliation: Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Klein
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Mathelier
authors.affiliation: Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Sliwa-Primorac
authors.affiliation: Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Ma
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: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Shin
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Michito
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Lizio
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Itoh
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Kawaji
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; Telethon Kids Institute, The University of Western Australia, Subiaco, WA 6008, Australia.
authors.forename: Timo
authors.initials: T
authors.lastname: Lassmann
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Carsten O
authors.initials: CO
authors.lastname: Daub
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.affiliation: Division of Genomic Technologies, RIKEN Center for Life Science 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: Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Alistair R R
authors.initials: ARR
authors.lastname: Forrest
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland. Electronic address: michael.detmar@pharma.ethz.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D047108:Embryonic Development; D004729:Endothelium, Lymphatic / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism; D051258:MafB Transcription Factor / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D059467:Transcriptome; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3